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Mechanisms of Arrhythmias and Defibrillation in Ischemia

缺血时心律失常和除颤的机制

基本信息

批准号：
7119840
负责人：
STEPHEN B KNISLEY
金额：
$ 3.68万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-30 至 2006-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7119840
关键词：
arrhythmia benzopyrans electric countershock heart resuscitation epicardial mapping fluorescent dye /probe heart electrical activity laboratory rabbit laboratory rat membrane potentials myocardial ischemia /hypoxia optics potassium channel tissue /cell culture vasodilators

项目摘要

Ischemia introduces arrhythmias and may increase defibrillation threshold. TO improve understanding and treatment of patients with ischemia, knowledge of the mechanisms for the arrhythmias and for defibrillation threshold changes during ischemia is needed. This project will test the hypotheses that 1) the gradient of transmembrane potential and curvature of the regional ischemic border induce extrasystoles, and 2) ischemia reduces the transmembrane voltage changes produced by an electrical shock. We will test these hypotheses using optical mapping and fluorescence emission ratiometry with voltage-sensitive dyes in isolated hearts and myocyte cultures, histological examination of the ischemic border, and mathematical modeling with a biodomain representation of cardiac tissue containing realistic ischemic tissue resistances and geometry of the border. We will produce global and regional ischemia and components of the ischemia with epinephrine, elevated potassium, an ATP-dependent potassium channel opener (cromakalim), and a cellular uncoupler (palmitoleic acid). We will determine the dependence of extrasystoles on regional hyperkalemia and ischemia by measuring gradients of transmembrane potential across the ischemic or hyperkalemic border on epicardium and endocardium. Studies will emphasize border curvature as an important variable for focusing injury current, and will consider modulation of extrasystole induction by cellular uncoupling. Transmembrane voltage changes produce by an electrical shock during ischemia will be considered in terms of membrane resistance modulation by elevated potassium and by ATP-dependent potassium channel opening. Separate studies will consider cellular uncoupling. The understanding of the mechanisms of extrasystoles and defibrillation during ischemia gained from this project will help in the diagnosis and emergency treatment of patients who undergo arrhythmias or sudden cardiac death soon after acute myocardial ischemia.

缺血引起心律失常，并可能增加除颤阈值。为了提高对缺血患者的理解和治疗，需要了解缺血期间心律失常和除颤阈值变化的机制。本项目将测试以下假设：1）跨膜电位梯度和局部缺血边界的曲率诱导期外收缩，以及2）缺血降低电击产生的跨膜电压变化。我们将测试这些假设，使用光学映射和荧光发射比率法与电压敏感染料在离体心脏和心肌细胞培养，缺血边界的组织学检查，和数学建模与生物域表示的心脏组织，包含现实的缺血组织电阻和几何形状的边界。我们将用肾上腺素、钾升高、ATP依赖性钾通道开放剂（cromakalim）和细胞解偶联剂（棕榈油酸）产生全局和局部缺血以及缺血组分。我们将通过测量心外膜和心内膜缺血或高钾边界的跨膜电位梯度来确定期外收缩对局部高钾血症和缺血的依赖性。研究将强调边界曲率作为聚焦损伤电流的重要变量，并将考虑细胞解偶联对期前收缩诱导的调制。在局部缺血期间由电击产生的跨膜电压变化将被认为是由升高的钾和ATP依赖性钾通道开放引起的膜电阻调节。单独的研究将考虑细胞解偶联。本研究对缺血期外收缩和除颤机制的认识将有助于急性心肌缺血后心律失常或心源性猝死患者的诊断和急救。