Cellular Basis for Autonomic Regulation of Cardiac Arrhythmias

心律失常自主调节的细胞基础

• 批准号: 10627578
• 负责人: ROBERT D HARVEY
• 金额: $ 39.03万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627578
• 关键词: Acetylcholine; Action Potentials; Adrenergic Agents; Affect; American; Anatomy; Animal Model; Area; Arrhythmia; Biochemical; Cardiac; Cell Separation; Cells; Chronic; Computer Models; Data; Dependence; Disease; Electrophysiology (science); Event; Family suidae; Foundations; Generations; Heart; Heart Transplantation; Heart failure; Heterogeneity; Human; Incidence; Individual; Infarction; Ion Channel; Life; Link; Measures; Mediating; Miniature Swine; Modeling; Molecular Biology; Muscle Cells; Myocardial Infarction; Myocardium; Nerve; Neurotransmitters; Norepinephrine; Patch-Clamp Techniques; Persons; Prevention; Property; Recovery; Regulation; Role; Techniques; Testing; Therapeutic; Tissue Survival; Tissues; Transplantation; Vasoactive Intestinal Peptide; Ventricular; Ventricular Arrhythmia; Vision; autonomic nerve; electrical property; experimental study; healing; heart electrical activity; immunocytochemistry; improved; neuropeptide Y; neuroregulation; pharmacologic; prevent; programs; response; sudden cardiac death; translational study; Acetylcholine; Action Potentials; Adrenergic Agents; Affect; American; Anatomy; Animal Model; Area; Arrhythmia; Biochemical; Cardiac; Cell Separation; Cells; Chronic; Computer Models; Data; Dependence; Disease; Electrophysiology (science); Event; Family suidae; Foundations; Generations; Heart; Heart Transplantation; Heart failure; Heterogeneity; Human; Incidence; Individual; Infarction; Ion Channel; Life; Link; Measures; Mediating; Miniature Swine; Modeling; Molecular Biology; Muscle Cells; Myocardial Infarction; Myocardium; Nerve; Neurotransmitters; Norepinephrine; Patch-Clamp Techniques; Persons; Prevention; Property; Recovery; Regulation; Role; Techniques; Testing; Therapeutic; Tissue Survival; Tissues; Transplantation; Vasoactive Intestinal Peptide; Ventricular; Ventricular Arrhythmia; Vision; autonomic nerve; electrical property; experimental study; healing; heart electrical activity; immunocytochemistry; improved; neuropeptide Y; neuroregulation; pharmacologic; prevent; programs; response; sudden cardiac death; translational study

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.

项目摘要/摘要 - 项目2 心脏猝死（SCD）描述了心室心律不齐的突然发作，杀死了更多的美国人 比任何其他疾病。人们经常观察到这些威胁生命的电活动变化 患有先前心肌梗塞（MI）的人。不幸的是，我们预防SCD的能力受到 对实际触发潜在心律不齐的原因的理解不完整。存活的组织 围绕心脏的梗塞区域，被称为边界区域，是重入的主要视线 维持这些事件的电活动。在边界区发现的肌细胞的电气异质性 心肌的偏远区域创造了重新进入的基板。但是，一代 与SCD相关的心律不齐也与同情语调的增加有关 副交感神经。实际上，已证明慢性迷走神经刺激（CVN）降低了发生率 MI后心律不齐的心律失常。然而，尚不知道肌细胞如何在该区域的不同区域发现 梗塞心脏对自主神经递质（例如去甲肾上腺素（NE）和乙酰胆碱（ACH））的反应。 此外，有证据表明心律不齐的发生率也受共释司机的释放影响 例如神经肽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， 通过调节电异质性以及 触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和如何 VIP影响心室肌细胞的电性能，2）做交感神经和副交感神经 神经递质会影响边界区域内肌细胞的电性异质性和触发活性 梗塞心脏的偏远区域不同，3）CVN会通过重塑而减少心律失常 梗塞心脏中肌细胞的电气和药理特性。单细胞的组合 电生理学，分子生物学，免疫细胞化学和生化技术将用于 回答这些问题。该项目中确定的细胞级别发生的变化将与 有关在整个心脏上观察到的自主神经的分布和功能变化的信息 该计划项目的项目2和3中的级别通过使用计算建模方法来调查 心律不齐的自主性调节的机理基础。该项目的结果将为基础提供 可以从中可以从中进行机理评估靶向神经调节的功效，从而改善 预防SCD的治疗策略。