SCOR IN SUDDEN CARDIAC DEATH

本SCOR应用程序的长期目标是调查 心源性猝死的致瘤机制 冠心病和心室肥厚患者。这些 两种疾病是造成300，000例突发性 美国每年的心脏病死亡人数。贯穿于所有的主题 研究表明，心肌结构异常， 细胞间通讯导致电生理紊乱 导致心律失常其中一些异常，一旦 可以纠正或修改，消除或减少 心律失常的频率。此外，认识到这些 动物模型中的异常将导致特异性增加， 识别有心源性猝死风险的患者的敏感性， 新的治疗干预。通过互动和协作 研究中，我们将遵循以下四个主要假设：1） 心肌重塑改变了心肌细胞的数量、分布或功能， 几个重要的心脏结构，包括间隙连接和 自主神经支配模式，直接或间接地 负责正常的细胞间通讯; 2）这些改变 在缝隙连接和神经支配模式是不同的， 并产生不同的电生理模式， 导致不同机制的室性心律失常; 3）纠正 这些异常与基因工程细胞将恢复 电生理朝着正常模式，并帮助防止发展 室性心律失常;和4）建立模式， 动物的神经支配和细胞间通讯异常 模型将提供深入了解识别和治疗患者， 心源性猝死的风险。六个项目和两个核心已经 为实现这些目标而努力。项目1（Pressler）确定 并试图修复间隙连接的异常;项目2（华纳） 确定并尝试修复自主神经支配的改变 和电生理学;项目3（现场）使用心内移植 技术在努力影响心肌再生和长期 递送心脏保护化合物以修复或纠正 潜在的异常;项目4（哈钦斯）连接动物和 通过提供非侵入性的成像模式， 交感神经和毒蕈碱神经支配以及一般心肌 功能;项目5（Mulholland）开发新的PET示踪剂， 心肌和神经支配异常;以及项目6（Zipes） 与所有项目进行交互，并调查自主和 冠心病患者的电生理模式， 心室肥大核心包括组织病理学核心 （Pressler）将提供组织组织学资源， 管理核心（Zipes），负责 的SCOR。该SCOR应用程序结合了分子生物学的方法， 生物学和蛋白质生物化学与体外和体内动物 电生理学研究，以探索和了解原因 和心律失常的机制，负责心脏性猝死， 患者

The long term objective of this SCOR application is to investigate the arrhythmogenic mechanisms responsible for sudden cardiac death in patients with coronary heart disease and ventricular hypertrophy. These two disorders are responsible for the vast majority of the 300,000 sudden cardiac deaths annually in the US. The unifying theme through all of the studies is that structural abnormalities of the myocardium that affect cell-to-cell communication lead to electrophysiological disturbances responsible for cardiac arrhythmias. Some of these abnormalities, once identified, can be corrected or modified, with elimination or reduction in the frequency of cardiac arrhythmias. Further, recognition of these abnormalities in animal models will lead to increased specificity and sensitivity in identifying patients at risk for sudden cardiac death and to new therapeutic interventions. Through interactive and collaborative studies, we will pursue the following four major hypotheses: 1) myocardial remodeling alters the number, distribution or function of several important cardiac structures, including gap junctions and autonomic innervation patterns, that are directly and indirectly responsible for normal cell-to-cell communication; 2) these alterations in gap junctions and innervation patterns are different in the various cardiomyopathies and produce different electrophysiological patterns that result in ventricular arrhythmias of different mechanisms; 3) correction of these abnormalities with genetically-engineered cells will restore the electrophysiology toward normal patterns and help prevent the development of ventricular arrhythmias; and 4) establishing the patterns of abnormalities in innervation and cell-to-cell communication in the animal models will provide insight into identifying and treating patients at risk for sudden cardiac death. Six projects and 2 cores have been assembled to address these objectives. Project 1 (Pressler) identifies and attempts to repair abnormalities in gap junctions; Project 2 (Warner) identifies and attempts to repair alterations in autonomic innervation and electrophysiology; Project 3 (Field) uses intracardiac grafting techniques in an effort to effect myocardial regeneration and long term delivery of cardioprotective compounds to repair or correct the underlying abnormalities; Project 4 (Hutchins) bridges the animal and clinical projects by providing noninvasive imaging patterns of sympathetic and muscarinic innervation as well as general myocardial function; Project 5 (Mulholland) develops new PET tracers to study abnormalities of the myocardium and innervation; and Project 6 (Zipes) interacts with all projects and investigates the autonomic and electrophysiologic patterns in a patients with coronary disease and ventricular hypertrophy. The cores include a histopathology core (Pressler) that will provide tissue histology resources, and an administration core (Zipes) responsible for the day-to-day operation of the SCOR. This SCOR application combines the methodologies of molecular biology and protein biochemistry with in vitro and in vivo animal electrophysiology studies in order to explore and understand the causes and mechanisms of arrhythmias responsible for sudden cardiac death in patients.