Myocardial ischemia remodels the cardiac nervous system

描述（由申请人提供）：神经体液控制的不平衡，尤其是导致交感传出神经元过度激活的不平衡，与心脏功能的短期和长期不良改变相关，包括心律失常和泵衰竭。作为推论，稳定心脏神经元层次结构的选定组成部分内的这种不平衡可以减少心律失常的基础，维持心肌细胞的活力并延长生存期。因此，这种竞争性更新的主要目标是首先确定心脏神经元层次结构的中枢和外周成分内部和之间相互依赖的相互作用的作用，其次确定这种联系如何响应急性和慢性心脏应激（例如心肌缺血/梗塞）而重塑。由于内在心脏神经系统代表心脏控制的最终共同整合器，因此心脏神经元层次结构的这个器官组成部分代表了靶向神经调节治疗的主要焦点。我们假设慢性心肌梗死/缺血会重塑外周（内在心脏和胸腔外心脏）神经系统，从而导致心律失常的发生和收缩功能的恶化。我们进一步假设，靶向神经调节可减轻缺血引起的心脏内在和心脏外胸内神经系统的重塑，从而减少心律失常形成的基础，同时维持收缩功能。该资助利用了通过脊髓刺激 (SCS) 进行电神经调节所提供的机会，这是一种具有公认的抗抗原特性的临床疗法，这种治疗方法具有治疗 i) 心律失常和 ii) 充血性心力衰竭的潜力。心脏神经元层级内的中央连接点将受到电刺激（背侧 T1-T3 SCS），以调节内在心脏神经系统，从而影响区域心脏电稳定性并支持收缩功能。具体目标 1 将确定 a) 局部心房电事件如何通过内在心脏神经元活动进行协调，从而使其选择的神经输入过度激活导致房性心律失常；b) 慢性 SCS 是否会改变内在心脏神经系统内的胆碱能和非胆碱能突触相互作用以减少这种致心律失常的可能性。具体目标 2 将确定 a) 慢性心肌梗塞/缺血是否会重塑内在心脏神经系统，从而使导致房性心律失常的神经元底物增强，然后测试 b) 慢性 SCS 改变内在心脏神经系统内突触相互作用以抑制房性心律失常的能力。具体目标 3 将确定慢性心肌梗塞/缺血是否会不利地重塑内在心脏和心脏外胸腔内自主神经功能，从而导致心脏机械功能恶化，如果是这样，慢性 SCS 是否会减轻这种变化。

DESCRIPTION (provided by applicant): Imbalances in neurohumoral control, especially those leading to excessive sympathetic efferent neuronal activation, are associated with adverse short- and long-term alterations in cardiac function - including cardiac arrhythmias and pump failure. As a corollary, stabilization of such imbalances within select components of the cardiac neuronal hierarchy can reduce the arrhythmic substrate, maintain myocyte viability and prolong survival. Thus, the primary objective for this competitive renewal is to first determine the role of interdependent interactions within and between central and peripheral components of the cardiac neuronal hierarchy and secondly how such linkages remodel in response to acute and chronic cardiac stress (e.g. myocardial ischemia/infarction). As the intrinsic cardiac nervous system represents the final common integrator of cardiac control, this organ component of the cardiac neuronal hierarchy represents a primary focus for targeted neuromodulation therapy. We hypothesize that chronic myocardial infarction/ischemia remodels the peripheral (intrinsic cardiac and extra cardiac intrathoracic) nervous system, thereby contributing to both the genesis of cardiac arrhythmias and deterioration of contractile function. We further hypothesize that targeted neuromodulation mitigates ischemia-induced remodeling of the intrinsic cardiac and extra cardiac intrathoracic nervous systems, thereby reducing the substrate for cardiac arrhythmia formation while sustaining contractile function. This grant exploits the opportunities afforded by electrical neuromodulation via spinal cord stimulation (SCS), a clinical therapy with recognized anti-antiginal properties - a therapeutic approach that has potential for management of both i) arrhythmias and ii) congestive heart failure. Central nexus points within the cardiac neuronal hierarchy will be stimulated electrically (dorsal T1-T3 SCS) to modulate the intrinsic cardiac nervous system to impact regional cardiac electrical stability and support contractile function. Specific aim 1 will determine a) how regional atrial electrical events are coordinated by the intrinsic cardiac neuronal activity such that excessive activation of its select nerve inputs lead to atrial arrhythmias and b) if chronic SCS modifies cholinergic and noncholinergic synaptic interactions within the intrinsic cardiac nervous system to reduce this arrhythmogenic potential. Specific aim 2 will determine a) if chronic myocardial infarction/ischemia remodels the intrinsic cardiac nervous system such that this atrial arrhythmogenic neuronal substrate becomes enhanced and then to test the capacity of b) chronic SCS to modify synaptic interactions within the intrinsic cardiac nervous system in the suppression of atrial arrhythmias. Specific Aim 3 will determine if chronic myocardial infarction/ischemia adversely remodels intrinsic cardiac and extra cardiac intrathoracic autonomic neural function, thereby contributing to deterioration of cardiac mechanical function and, if so, whether chronic SCS mitigates such changes.