Autonomic remodeling and modulation therapy in heart failure and sudden death

 描述（由申请人提供）：在美国，心脏性猝死（SCD）每年夺去25万人的生命。患有心力衰竭（HF）的个体患SCD的风险较高。HF和SCD之间的机制联系尚未确定。HF和SCD的标志是自主神经功能障碍。虽然β-肾上腺素能（交感神经）信号已在HF中得到广泛研究，但对毒蕈碱（副交感神经）信号的作用知之甚少。PI最近的研究表明，毒蕈碱受体的重塑是HF病理生理学的关键组成部分。此外，心脏复律治疗（CRT）（唯一改善急性和慢性心脏功能和存活的HF治疗）差异性地重塑毒蕈碱受体以改善交感迷走神经平衡、β-肾上腺素能反应性、Ca+2处理和收缩。迷走神经刺激（VNS）治疗对HF患者具有有益的效果，与CRT相似。其潜在机制在很大程度上是未知的。该提议利用了一种新型的肥厚性心力衰竭豚鼠模型，该模型概括了人类HF的许多特征，包括QT间期延长和自发性心肌SCD的高发生率。使用这种独特的模型，PI的新发现和VNS，一种有前途的新的HF治疗，该提案将测试的假设，即时间依赖性变化的mAChR的表达和信号在HF/SCD的发展中发挥关键作用，这些可以逆转慢性VNS。具体的目标将探索新的基本机制信息如何以及何时在疾病过程中mAChR重塑可能是有益的或病理性的，同时测试令人兴奋的HF/SCD新疗法。我们将使用差异转录组学和蛋白质组学（“组学”）鉴定慢性VNS修饰的关键蛋白质、途径和生物标志物。肌细胞特性的变化表现在转录组和蛋白质组中，促成HF/SCD表型。超声心动图、连续ECG和体内血流动力学研究将与分子/细胞研究平行进行。在离体研究中，抗体和药理学试剂将用于测试关键信号传导组分。该计划是PI长期目标的一部分，旨在研究心脏功能的分子机制，以开发新的令人兴奋的HF和SCD治疗方法。

 DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) claims a quarter millions lives per year in the United States. Individuals with heart failure (HF) are at a higher risk for SCD. The mechanistic link between HF and SCD has not been determined. The hallmark of HF and SCD is autonomic dysfunction. Whereas β-adrenergic (sympathetic) signaling has been extensively studied in HF, relatively little is known about the role of muscarinic (parasympathetic) signaling. Recent work by the PI has demonstrated that remodeling of muscarinic receptors is a critical component of the pathophysiology of HF. Further, cardiac resynchronization therapy (CRT), the only HF therapy to improve both acute and chronic cardiac function and survival differentially remodels muscarinic receptors to improve sympathovagal balance, β-adrenergic responsiveness, Ca+2 handling and contraction. Therapy with vagus nerve stimulation (VNS) has salutary effects in HF patients, similar to CRT. The underlying mechanisms are largely unknown. This proposal leverages a novel guinea pig model of hypertrophic heart failure that recapitulates many features of human HF, including prolonged QT interval and a high incidence of spontaneous arrhythmic SCD. Using this unique model, the PI's novel findings and VNS, a promising new HF therapy, this proposal will test the hypothesis that time-dependent changes in mAChR expression and signaling play a critical role in the development of HF/SCD and these can be reversed by chronic VNS. The specific aims will explore new fundamental mechanistic information about how and when in the disease process mAChR remodeling may be beneficial or pathological, while testing exciting new therapies for HF/SCD. We will identify key proteins, pathways and biomarkers modified by chronic VNS using differential transcriptomics and proteomics ("omics"). Changes in myocyte properties are manifested in transcriptome and proteome, contributing to the HF/SCD phenotype. Echocardiography, continuous ECG and in vivo hemodynamic studies will parallel the molecular/cellular studies. In ex vivo studies, antibodies and pharmacological agents will be used to test key signaling components. The proposed program is part of the PI's long term goal to investigate molecular mechanisms of cardiac function for the development of new exciting therapies for HF and SCD.