Myocardial ischemia remodels the cardiac nervous system

描述（由申请人提供）：神经体液控制失衡，尤其是导致交感传出神经元过度激活的失衡，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。作为一个必然的结果，稳定心脏神经元层次的选择组件内的这种不平衡可以减少心肌基质，维持肌细胞活力和延长生存。因此，这种竞争性更新的主要目的是首先确定心脏神经元层级的中央和外周成分内部和之间的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/梗死）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者，因此心脏神经元层级的该器官组分代表靶向神经调节治疗的主要焦点。我们假设慢性心肌梗死/缺血重塑外周（内在心脏和心外胸内）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，靶向神经调节减轻缺血诱导的内源性心脏和心外胸内神经系统重塑，从而减少心律失常形成的底物，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治疗方法-一种有潜力管理i）心律失常和ii）充血性心力衰竭的治疗方法。将对心脏神经元层级内的中枢神经点进行电刺激（背侧T1-T3 SCS），以调节心脏固有神经系统，从而影响局部心脏电稳定性并支持收缩功能。具体目标1将确定a）区域心房电事件如何通过内在心脏神经元活动协调，从而其选择神经输入的过度激活导致房性心律失常，以及B）慢性SCS是否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，以降低该致心律失常电位。具体目标2将确定a）慢性心肌梗死/局部缺血是否重塑内在心脏神经系统，使得该心房致心律失常神经元基质变得增强，然后测试B）慢性SCS在抑制房性心律失常中改变内在心脏神经系统内的突触相互作用的能力。具体目标3将确定慢性心肌梗死/缺血是否会对心脏固有和心外胸内自主神经功能造成不良重塑，从而导致心脏机械功能恶化，如果是，慢性SCS是否会减轻此类变化。 公共卫生相关性：心脏神经系统的中枢和外周方面之间的相互作用在正常和应激心脏的控制中起主要作用。该系统内的不平衡与包括异常心跳、心脏性猝死和心力衰竭在内的有害影响相关。支持这一建议的基本概念是：1）了解心脏神经元层次的中枢和外周成分内部和之间发生的相互依赖的相互作用; 2）确定这种联系如何在慢性心脏应激反应中重塑（例如心肌缺血/梗死）;和3）以确定针对心脏神经系统的选择元件的最佳治疗策略，以减轻充血性心力衰竭的进展和心源性猝死

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. PUBLIC HEALTH RELEVANCE: Interactions between central and peripheral aspects of the cardiac nervous system play a major role in control of the normal and stressed heart. Imbalances within this system are associated with deleterious effects including abnormal heart beats, sudden cardiac death and heart failure. The fundamental concept underpinning this proposal is to: 1) understand the interdependent interactions occurring within and between central and peripheral components of the cardiac neuronal hierarchy; 2) to determine how such linkages remodel in response to chronic cardiac stress (e.g. myocardial ischemia/infarction); and 3) to determine what are the optimum therapeutic strategies to target select elements of the cardiac nervous system to mitigate the progression of congestive heart failure and the potential for sudden cardiac death.