Cellular Basis for Autonomic Regulation of Cardiac Arrhythmias

项目摘要/摘要--项目2 心脏性猝死(SCD)指的是导致更多美国人死亡的室性心律失常的突然发作 比其他任何疾病都要好。这些危及生命的电活动变化最常在人身上观察到 有心肌梗死(MI)史的患者。不幸的是，我们预防SCD的能力受到 对真正引发潜在心律失常的原因了解不够充分。幸存的组织 围绕着心脏梗死区，称为交界区，是折返者的主要视线。 维持这些事件的电活动。在交界区发现肌细胞的电异质性 而心肌更偏远的区域为再入创造了一个底物。然而，这一代 与SCD相关的心律失常也与交感神经张力增加和 副交感神经音调。事实上，慢性迷走神经刺激(CVNS)已经被证明可以减少这种情况的发生。 心肌梗塞后的室性心律失常。然而，目前尚不清楚心肌细胞是如何在大脑的不同区域发现的。 心肌梗死对去甲肾上腺素(NE)和乙酰胆碱(ACh)等自主神经递质有反应。 此外，有证据表明，心律失常的发生率也受到共同递质释放的影响。 如神经肽Y(NPY)和血管活性肠肽(VIP)。我们的工作假设是 交感神经递质NE和NPY以及副交感神经递质ACh和VIP， 通过调节电的异质性改变梗塞心脏的致心律失常潜能 引发了不同地区的活动。在这个项目中，我们将解决以下问题：1)NPY和 血管活性肠肽影响心室肌细胞的电特性，2)交感神经和副交感神经 神经递质影响交界区和交界区肌细胞的电异质性和触发活动 3)CVN是否通过重塑心脏节律减少心律失常的发生？ 心肌梗死后心肌细胞的电学和药理学特性。单个细胞的组合 将使用电生理学、分子生物学、免疫细胞化学和生化技术来 回答这些问题。在本项目中确定的蜂窝级别发生的变化将与 关于在整个心脏观察到的自主神经分布和功能变化的信息 在本计划项目的项目2和项目3中使用计算建模方法来调查 心律失常自主调节的机制基础。本项目的成果将为今后的工作奠定基础 由此可以机械地评估靶向神经调节的有效性，从而导致改善 预防SCD的治疗策略。

PROJECT SUMMARY/ABSTRACT - Project 2 Sudden cardiac death (SCD) describes the abrupt onset of ventricular arrhythmias that kills more Americans than any other disease. These life-threatening changes in electrical activity are most often observed in people who have suffered a prior myocardial infarction (MI). Unfortunately, our ability to prevent SCD is limited by an incomplete understanding of what actually triggers the underlying arrhythmias. The surviving tissue surrounding the infarcted area of the heart, known as the border zone, is the primary sight of reentrant electrical activity that sustains these events. Electrical heterogeneities in myocytes found in the border zone and more remote areas of the myocardium create a substrate for reentry. However, the generation of arrhythmias associated with SCD is also linked to an increase in sympathetic tone and a decrease in parasympathetic tone. In fact, chronic vagal nerve stimulation (cVNS) has been shown to reduce the incidence of ventricular arrhythmias following an MI. Yet, it is not known how myocytes found in different areas of the infarcted heart respond to autonomic neurotransmitters such as norepinephrine (NE) and acetylcholine (ACh). Furthermore, there is evidence the incidence of arrhythmias is also affected by the release of co-transmitters such as neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). Our working hypothesis is that the sympathetic neurotransmitters NE and NPY, as well as the parasympathetic neurotransmitters ACh and VIP, alter the arrhythmogenic potential of the infarcted heart by regulating electrical heterogeneity as well as triggered activity in different areas. In this Project, we will address the following questions: 1) how do NPY and VIP affect the electrical properties of ventricular myocytes, 2) do sympathetic and parasympathetic neurotransmitters affect electrical heterogeneity and triggered activity of myocytes in the border zone and remote areas of the infarcted heart differently, and 3) does cVNS reduce arrhythmogenesis by remodeling the electrical and pharmacological properties of myocytes in the infarcted heart. A combination of single cell electrophysiology, molecular biology, immunocytochemistry, and biochemical techniques will be used to answer these questions. Changes occurring at the cellular level identified in this Project will be integrated with information about changes in the distribution and function of autonomic nerves observed at the whole heart level in Projects 2 and 3 of this Program Project by using a computational modeling approach to investigate the mechanistic basis for autonomic regulation of arrhythmias. The results of this project will provide the foundation from which the efficacy of targeted neuromodulation can be mechanistically assessed, leading to improved therapeutic strategies for preventing SCD.