Myocardial ischemia remodels the cardiac nervous system

描述(申请人提供)：神经体液控制的失衡，特别是那些导致交感传出神经元过度激活的失衡，与心功能的不利短期和长期变化有关-包括心律失常和泵衰竭。作为推论，稳定心脏神经元结构中特定成分内的这种失衡可以减少心律失常的底物，维持心肌细胞的活力，并延长存活时间。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的中枢和外周成分之间相互依赖的相互作用的作用，其次确定这种联系如何重塑以应对急性和慢性心脏应激(例如心肌缺血/梗死)。由于心脏固有神经系统代表心脏控制的最终共同积分器，心脏神经元层次的这一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/缺血重塑外周(心脏内和胸外)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，靶向神经调节减轻了缺血诱导的心脏内和胸外神经系统的重构，从而减少了心律失常形成的底物，同时保持了收缩功能。这笔赠款利用了通过脊髓刺激(SCS)进行神经电调节所提供的机会，SCS是一种具有公认的抗抗药特性的临床疗法，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。心脏神经层级内的中枢连接点将受到电刺激(背侧T1-T3SCS)来调节心脏固有神经系统，以影响局部心脏的电稳定和支持收缩功能。具体目标1将决定a)局部心房电活动如何与心脏固有神经元活动相协调，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是否改变了心脏固有神经系统内胆碱能和非胆碱能突触的相互作用，以降低这种致心律失常的潜力。具体目标2将确定a)慢性心肌梗死/缺血是否重塑心脏固有神经系统，从而使房性心律失常致神经元底物增强，然后测试b)慢性SCS在抑制房性心律失常中改变心脏固有神经系统内突触相互作用的能力。具体目标3将确定慢性心肌梗死/缺血是否对心脏内和心外自主神经功能产生不利影响，从而导致心脏机械功能的恶化，如果是，慢性心肌梗死/缺血是否减轻这种变化。

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.