Myocardial Ischemia Remodels the Cardiac Nervous System

描述（由申请人提供）：本提案的总体目标是确定心脏神经元层次如何调节缺血心肌中的电事件。我们假设，不同水平的心脏神经元所引起的反射反应的异质性可能导致该系统被过度缺血诱导的传入输入所淹没。由此产生的外周和中枢成分之间信息处理的不平衡导致儿茶酚胺在心室内释放的异质性，从而加剧心律失常形成的底物。我们假设中枢神经系统（脊髓）神经元亚群的作用是稳定胸内心脏神经元层次的某些组成部分，以抑制不均匀的交感神经输出输入到心脏，从而降低心律失常的易感性。为了实现这一目标，我们建议确定：1)传入神经元如何将正常和缺血心肌的环境转导到心脏神经元层级中的二级神经元；2)这些信息如何影响胸内局部回路神经元，最终协调输出神经元向心脏的流出；3)胸脊髓神经元如何稳定这些信息的处理。具体目标1。目的：确定短暂性心室缺血反射反应中伴随不同区域儿茶酚胺释放到心脏间质的区域心电事件弥散的关系，包括确定这种弥散的中枢和外周反射处理的贡献。具体目标2。为了确定心脏神经元层级中不同水平的心脏传入神经元如何将正常灌注与缺血心肌的机械和化学环境差异转导到二级神经元，并确定不同胸内神经元亚型（传入、传出和局部回路神经元）表达的形态学和神经化学编码。具体目标3。确定脊髓神经元减轻这种心肌缺血诱导的儿茶酚胺反射释放到不同左室区域的能力，从而减弱任何由此产生的心脏电生理特性的有害差异。这将包括确定中央诱导的交感神经和迷走神经下降投射对胸内神经系统的内在贡献，以减轻由这种状态引起的不良心脏电事件。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to determine how the cardiac neuronal hierarchy modulates electrical events in the ischemic myocardium. We hypothesize that heterogeneity of reflex responses evoked by neurons at different levels of the cardiac neuronal hierarchy can result in this system becoming overwhelmed by excessive ischemia-induced afferent inputs. The resultant imbalance of information processing between its peripheral and central components induces heterogeneity of catecholamine release within the ventricle to exacerbate the substrate for arrhythmia formation. We hypothesize that subpopulations of CNS (spinal cord) neurons act to stabilize select components of the intrathoracic cardiac neuronal hierarchy to suppress inhomogeneous sympathetic efferent neuronal inputs to the heart, thereby reducing arrhythmia susceptibility. In order to accomplish this objective, we propose to determine: 1) How the milieu of the normal and ischemic myocardium is transduced by afferent neurons to second order neurons throughout the cardiac neuronal hierarchy; 2) How that information impinges on intrathoracic local circuit neurons that ultimately coordinate efferent neuronal outflows to the heart; and 3) How thoracic spinal cord neurons stabilize the processing of such information. Specific aim 1. To determine the relationship of dispersion of regional cardiac electrical events concomitant with differential regional catecholamine release into the cardiac interstitium in reflex response to transient ventricular ischemia, including determining the contribution of central versus peripheral reflex processing of such dispersion. Specific aim 2. To determine how cardiac afferent neurons at different levels' in the cardiac neuronal hierarchy differentially transduce the mechanical and chemical milieu of the normally perfused versus ischemic myocardium to second order neurons and to determine the morphology and neurochemical coding expressed by the different intrathoracic neuronal subtypes (afferent, efferent, and local circuit neurons) involved. Specific aim 3. To determine the capacity of spinal cord neurons to mitigate such myocardial ischemia-induced reflex release of catecholamines into disparate LV regions to thereby blunt any resultant deleterious disparity of cardiac electrophysiological properties. This will include determining the inherent contributions of centrally-induced changes in sympathetic versus vagal descending projections to the intrathoracic nervous system in mitigating untoward cardiac electrical events initiated by such a state.