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，心脏神经元层次不同水平的神经元所引起的反射反应的异质性可以导致该系统被过度的缺血诱导的传入输入所淹没。其外周和中枢成分之间的信息处理失衡导致脑室内儿茶酚胺释放的异质性，从而加剧心律失常形成的底物。我们假设，CNS(脊髓)神经元亚群的作用是稳定胸腔内心脏神经元层次的特定成分，以抑制不均匀的交感传出神经元对心脏的输入，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传递到整个心脏神经元层级的二阶神经元；2)该信息如何影响到胸腔内局部环路神经元，最终协调传出神经元向心脏的流出；以及3)胸段脊髓神经元如何稳定这些信息的处理。具体目的1.确定短暂性心室缺血反射反应中伴随局部心电活动的离散度与局部儿茶酚胺释放到心脏间质的差异性之间的关系，包括确定这种离散度在中枢和外周反射过程中的作用。具体目的2.确定不同水平的心脏传入神经元如何将正常灌流心肌和缺血心肌的机械和化学环境差异地传递给二级神经元，并确定不同的胸内神经元亚型(传入、传出和局部环路神经元)所表达的形态和神经化学编码。具体目的3.确定脊髓神经元的能力，以减轻这种心肌缺血诱导的反射性释放儿茶酚胺到不同的左室区域，从而钝化任何由此产生的心脏电生理特性的有害差异。这将包括确定中枢诱导的交感神经与迷走神经下行投射到胸腔内神经系统的变化在减轻由这种状态引发的不适心脏电事件方面的内在贡献。

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.