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Cardiac Afferent Neurotransmission and Modulation of Ventricular Parasympathetic Control

心脏传入神经传递和心室副交感神经控制的调节

基本信息

批准号：
8955607
负责人：
Marmar Vaseghi
金额：
$ 231万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) due to ventricular tachyarrhythmias (VT) is the leading cause of mortality in the United States, resulting in 250,000 deaths/year. Implantable cardiac defibrillators (ICD) have been the primary bailout treatment strategy for patients with VT. Despite optimum medical therapy and targeted catheter ablation, 20-50% of patients can expect to have recurrent VT and ICD shocks at one year, decreasing quality of life and increasing mortality. Cardiac autonomic dysregulation, characterized by (i) excessive sympathetic activation and (ii) diminished parasympathetic response are central to the pathogenesis of cardiomyopathy and VT. Blockade of sympathetic activation has been the focus of current therapies for cardiomyopathy and arrhythmias. However, significant abnormalities in parasympathetic activity also accompany cardiomyopathy and have been demonstrated to increase risk of arrhythmias and SCD. There is a huge knowledge gap as to why parasympathetic dysfunction occurs. Our laboratory recently has determined that the acetylcholine content in the border zones and viable regions of infarcted hearts are similar if not greater than normal hearts. Thus, the diminished parasympathetic response post myocardial infarction (MI) occurs despite ample cardiac neurotransmitter levels. The primary and unique hypothesis of this proposal is that MI leads to a decrease in central parasympathetic drive to the heart due to altered cardiac afferent signaling (caused by the infarct itself). This proposal, for he first time, will determine the maladaptive alterations in vagal afferent signaling in a conscious large animal chronic MI model and in humans with cardiomyopathy. Multi-electrode array neural recordings will be combined with simultaneous high-density electrophysiological mapping and direct neurotransmitter content measurements in basal and stressed conditions to assess autonomic remodeling and function. Based on this foundation, effects of emerging neuromodulatory therapies including vagal nerve stimulation and cardiac sympathetic denervation (which also alters cardiac afferents) can then be mechanistically evaluated. Some of the key challenges associated with human studies and conscious animal neural recordings have been overcome in my laboratory. Accomplishing the goals of this proposal will identify and classify new and traditional neural targets of therapy that are "game-changing," and has the potential of presenting disease-modifying life-saving therapies to patients in the United States and around the globe.

描述（由申请人提供）：室性快速性心律失常（VT）导致的心源性猝死（SCD）是美国的主要死亡原因，每年导致250，000例死亡。植入式心脏复律器（ICD）已成为VT患者的主要急救治疗策略。尽管有最佳的药物治疗和靶向导管消融，20-50%的患者预计在一年内会复发VT和ICD电击，降低生活质量并增加死亡率。以（i）过度交感神经激活和（ii）副交感神经反应减弱为特征的心脏自主神经失调是心肌病和VT发病机制的核心。阻断交感神经激活一直是目前治疗心肌病和心律失常的焦点。然而，副交感神经活动的显著异常也伴随心肌病，并已被证明会增加心律失常和SCD的风险。关于为什么会发生副交感神经功能障碍，存在巨大的知识缺口。我们的实验室最近已经确定，在梗塞心脏的边缘区和存活区的乙酰胆碱含量是相似的，比正常的心脏。因此，尽管心脏神经递质水平充足，但心肌梗死（MI）后副交感神经反应减弱。该建议的主要和独特的假设是，MI由于心脏传入信号的改变（由梗死本身引起）导致对心脏的中枢副交感神经驱动减少。这一建议，他第一次，将确定适应不良的改变迷走神经传入信号在一个有意识的大型动物慢性心肌梗死模型和人类心肌病。多电极阵列神经记录将与基础和应激条件下的同步高密度电生理标测和直接神经递质含量测量相结合，以评估自主神经重塑和功能。基于这一基础，新兴的神经调节疗法，包括迷走神经刺激和心脏交感神经去神经支配（也改变心脏传入）的影响，然后可以进行机械评估。一些与人类研究和有意识的动物神经记录相关的关键挑战已经在我的实验室中克服。实现该提案的目标将识别和分类“改变游戏规则”的新的和传统的神经治疗靶点，并有可能为美国和地球仪的患者提供改善疾病的救生治疗。