Myocardial Ischemia Remodels the Cardiac Nervous System

心肌缺血重塑心脏神经系统

• 批准号: 7210747
• 负责人: JEFFREY L ARDELL
• 金额: $ 34.61万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-05 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210747
• 关键词: Affect; Afferent Neurons; Anatomy; Animals; Arrhythmia; Cardiac; Catecholamines; Chara; Chemicals; Code; Computer information processing; Decentralization; Doctor of Philosophy; Event; Genes; Heart; Heterogeneity; Immunohistochemistry; In Vitro; Interneurons; Ischemia; Label; Measures; Mechanics; Mediating; Methods; Microdialysis; Microscopy; Morphology; Myocardial; Myocardial Ischemia; Nervous system structure; Neurons; Neurostimulation procedures of spinal cord tissue; Organ; Peripheral; Physiological reperfusion; Population; Predisposition; Process; Property; Reflex action; Reperfusion Therapy; Resistance; Risk Factors; Sensory; Spinal Cord; Spinal Ganglia; Stress; System; Thoracic spinal cord structure; Tissues; Tyrosine 3-Monooxygenase; Ventricular; density; dorsal horn; neurochemistry; response; sucking; sudden cardiac death; uptake

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.

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级如何调节缺血心肌中的电事件。我们假设，在不同层次的心脏神经元层次的神经元引起的反射反应的异质性可能会导致该系统变得不堪重负的过度缺血诱导的传入输入。由此产生的外周和中枢成分之间的信息处理不平衡诱导心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）神经元的亚群的作用，以稳定胸内心脏神经元层次的选择组件，以抑制不均匀的交感神经传出神经元输入到心脏，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）正常和缺血心肌的环境是如何通过传入神经元转导到整个心脏神经元层次的二级神经元的; 2）该信息如何影响胸内局部回路神经元，最终协调传出神经元流出到心脏;和3）胸脊髓神经元如何稳定这些信息的处理。具体目标1.确定在短暂性心室缺血的反射反应中，局部心脏电事件的离散度与不同的局部儿茶酚胺释放到心脏心房的关系，包括确定中枢与外周反射处理这种离散度的贡献。具体目标2。目的：研究不同层次的心脏传入神经元对正常灌注心肌和缺血心肌的机械和化学环境的影响，以及不同类型的胸内神经元（传入神经元、传出神经元和局部环路神经元）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心肌缺血诱导的儿茶酚胺反射释放到不同LV区域的能力，从而减弱心脏电生理特性的任何有害差异。这将包括确定中枢诱导的交感神经与迷走神经下行投射变化对胸内神经系统在减轻由这种状态引发的不良心脏电事件方面的固有贡献。