STRUCTURE/FUNCTION OF THE PACEMAKING AND CONDUCTION SYSTEM OF THE HEART

心脏起搏和传导系统的结构/功能

• 批准号: 7524595
• 负责人: IGOR R EFIMOV
• 金额: $ 36.66万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7524595
• 关键词: Abbreviations; Action Potentials; Anatomic structures; Animal Model; Arrhythmia; Autonomic nervous system; Biophotonics; Bypass; Cardiac; Cardiac Output; Cardiac conduction system; Cardiovascular system; Cell physiology; Characteristics; Complex; Condition; Connexin 43; Connexins; Coupling; Development; Disease; Dyes; Frequencies; Funding; Future; Gap Junctions; Gene Expression; Generations; Goals; Hand; Heart; Heart Atrium; Heart Rate; Heterogeneity; Human; Image; Imaging technology; In Vitro; Inferior; Ion Channel; Knowledge; Maps; Mediating; Modality; Molecular; Myocardium; Nodal; Optical Coherence Tomography; Optics; Oryctolagus cuniculus; Pacemakers; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Physiology; Predisposition; Preparation; Procedures; Property; Protein Isoforms; Proteins; Radiofrequency Interstitial Ablation; Range; Rate; Research; Sinoatrial Node; Site; Structure; System; Tachycardia; Testing; Tissue Engineering; Transitional Cell; Ventricular; Work; atrioventricular node; base; cell type; clinical Diagnosis; clinically relevant; density; electronic pacemaker; heart rhythm; implantable device; improved; novel; protein expression; receptor; restoration; three dimensional structure; tomography; voltage

DESCRIPTION (provided by applicant): The pacemaking and conduction system (PCS) of the heart is a profoundly complex structure orchestrating orderly contractions of the cardiac chambers by generating and transmitting action potentials at an appropriate rate, conduction velocity, and incorporating a delay between the chambers to allow for proper ventricular filling. The PCS has been extensively studied in many animal models, however, the clinical relevance of these studies is not entirely clear. In contrast, we propose to conduct these studies in the healthy and diseased human heart in vitro. As evident from developmental studies, the PCS initially forms as an anatomically and functionally continuous structure that is starkly different from working atrial and ventricular myocardium. Subsequently, several distinct cell types develop within the PSC to fulfill the different requirements of pacemaking and conduction properties. The atrio-ventricular junction (AVJ), for example, represents this complexity at its extreme. There is a nearly 100-fold difference in the conduction velocity between the anatomically adjacent compact AV node (~2-3 cm/sec) and the His-Purkinje network (up to 2.5 m/sec). Such a difference is required for the proper delay of excitation between the atria and ventricles, on the one hand, and the synchronized excitation of the ventricles, on the other hand. We hypothesize that this functional heterogeneity has both a structural and molecular basis as the heterogeneity of gene expression encoding gap junctions, ion channels, and receptors of the PCS provides the substrate for normal and abnormal pacemaking and conduction. In this project we will focus on the quantification of the three-dimensional structure and function of the human AVJ. We will use a multimodal biophotonic approach consisting of optical mapping (OM) with voltage-sensitive dye, optical coherence tomography (OCT), and 3D immunohistochemical mapping (IM) of proteins, which define intercellular coupling and cell types. The specific aims of the project are: (1) To investigate molecular, structural and functional mechanisms of the dual pathway AV conduction in the human heart as suggested by opposing protein expression patterns in adjacent anatomic structures; (2) To test the hypothesis that the AV conduction axis may bypass the compact AVN and that can be utilized in resynchronization therapy in hearts with intact slow pathway conduction; (3) To test the hypothesis that an autonomically modulated AVJ pacemaker can replace a sick SAN; (4) To elucidate the basic molecular and structural mechanisms predisposing up to 90,000 patients per year to AVN reentrant tachycardia. The long-term goal of this project is to develop a structure/function framework of the entire human cardiac PCS. During the present funding period we will focus our efforts on the human AVJ. Numerous studies have previously examined the contribution of various isoforms of connexins, ion channels, and receptors to cellular physiology in the cardiac PCS. We, on the other hand, aim to apply a systems physiology approach, to examine factors responsible for the stability of normal pacemaking and conduction, abnormal impulse generation and failed conduction, and arrhythmogenesis mediated by the autonomic nervous system. We will also explore the potential of novel optical coherence tomography (OCT) imaging technology for clinical diagnosis and cardiovascular research. We believe that quantitative knowledge of protein expression levels contributing to both normal and abnormal pacemaking and conduction could help to formulate future strategies for improved implantable devices as well as tissue engineering approaches in the treatment of heart rhythm disorders associated with the PCS. PUBLIC RELEVANCE: The pacemaking and conduction system (PCS) of the heart is a profoundly complex structure orchestrating orderly contractions of the cardiac chambers by generating and transmitting action potentials at an appropriate rate, conduction velocity, and incorporating a delay between the chambers to allow for proper ventricular filling. Abnormalities in the function of both the sino-atrial and atrio-ventricular nodes of the PCS can cause arrhythmias which are currently treated by electronic pacemakers and/or radio-frequency ablation procedures in up to 500,000 patients annually. The long-term goal of this project is to develop a structure/function framework of the entire human cardiac PCS. During the present funding period we will focus our efforts on the human atrioventricular junction (AVJ). Numerous studies have previously examined the contribution of various isoforms of connexins, ion channels, and receptors to cellular physiology in the cardiac PCS. We, on the other hand, aim to apply a systems physiology approach to examine factors responsible for the stability of normal pacemaking and conduction, abnormal impulse generation and failed conduction, and arrhythmogenesis mediated by the autonomic nervous system. We believe that quantitative knowledge of protein expression levels contributing to both normal and abnormal pacemaking and conduction could help to formulate future strategies for improved implantable devices as well as tissue engineering approaches in the treatment of heart rhythm disorders associated with the PCS.

描述（由申请人提供）：心脏的起搏和传导系统（PCS）是一个极其复杂的结构，通过以适当的速率、传导速度产生和传输动作电位，并结合动作电位之间的延迟来协调心室的有序收缩。室以允许适当的心室充盈。 PCS 已在许多动物模型中进行了广泛研究，然而，这些研究的临床相关性尚不完全清楚。相比之下，我们建议在健康和患病的人类心脏中进行体外这些研究。发育研究表明，PCS 最初形成为解剖学和功能上的连续结构，与工作的心房和心室心肌截然不同。随后，PSC 内发育出几种不同的细胞类型，以满足起搏和传导特性的不同要求。例如，房室交界处 (AVJ) 就体现了这种复杂性的极致。解剖学上相邻的紧凑型 AV 结（~2-3 cm/sec）和 His-Purkinje 网络（高达 2.5 m/sec）之间的传导速度存在近 100 倍的差异。一方面，需要这种差异来适当延迟心房和心室之间的兴奋，另一方面，需要心室的同步兴奋。我们假设这种功能异质性具有结构和分子基础，因为编码 PCS 间隙连接、离子通道和受体的基因表达异质性为正常和异常起搏和传导提供了基础。在这个项目中，我们将重点关注人类 AVJ 三维结构和功能的量化。我们将使用多模态生物光子方法，包括使用电压敏感染料的光学测绘 (OM)、光学相干断层扫描 (OCT) 和蛋白质的 3D 免疫组织化学测绘 (IM)，定义细胞间耦合和细胞类型。该项目的具体目标是：（1）研究人类心脏中双通路AV传导的分子、结构和功能机制，正如相邻解剖结构中相反的蛋白质表达模式所暗示的那样； (2) 检验 AV 传导轴可能绕过紧凑 AVN 并可用于慢通路传导完整的心脏的再同步治疗的假设； (3) 检验自主调节 AVJ 起搏器可以替代患病 SAN 的假设； (4) 阐明每年多达 90,000 名患者易患 AVN 折返性心动过速的基本分子和结构机制。该项目的长期目标是开发整个人类心脏PCS的结构/功能框架。在目前的资助期内，我们将把重点放在人类 AVJ 上。此前有大量研究探讨了连接蛋白、离子通道和受体的各种亚型对心脏 PCS 细胞生理学的贡献。另一方面，我们的目标是应用系统生理学方法，检查负责正常起搏和传导稳定性、异常脉冲产生和传导失败以及自主神经系统介导的心律失常发生的因素。我们还将探索新型光学相干断层扫描（OCT）成像技术在临床诊断和心血管研究中的潜力。我们相信，对影响正常和异常起搏和传导的蛋白质表达水平的定量了解有助于制定未来的策略，以改进可植入装置以及治疗与 PCS 相关的心律失常的组织工程方法。公众相关性：心脏的起搏和传导系统 (PCS) 是一个极其复杂的结构，通过以适当的速率、传导速度产生和传输动作电位，并在心室之间引入延迟，从而协调心室的有序收缩。适当的心室充盈。 PCS 窦房结和房室结功能异常可引起心律失常，目前每年有多达 500,000 名患者通过电子起搏器和/或射频消融手术治疗心律失常。该项目的长期目标是开发整个人类心脏PCS的结构/功能框架。在目前的资助期间，我们将重点关注人类房室交界处（AVJ）。此前有大量研究探讨了连接蛋白、离子通道和受体的各种亚型对心脏 PCS 细胞生理学的贡献。另一方面，我们的目标是应用系统生理学方法来检查负责正常起搏和传导稳定性、异常冲动产生和传导失败以及自主神经系统介导的心律失常发生的因素。我们相信，对影响正常和异常起搏和传导的蛋白质表达水平的定量了解有助于制定未来的策略，以改进可植入装置以及治疗与 PCS 相关的心律失常的组织工程方法。