Mechanisms of Arrhythmias and Defibrillation in Ischemia

缺血时心律失常和除颤的机制

• 批准号: 6391015
• 负责人: STEPHEN B KNISLEY
• 金额: $ 15.78万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6391015
• 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

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.

缺血会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，需要了解心律失常和缺血期间除颤阈值变化的机制。该项目将测试以下假设：1) 跨膜电位梯度和局部缺血边界曲率诱发早搏，2) 缺血减少电击产生的跨膜电压变化。我们将在离体心脏和心肌细胞培养物中使用电压敏感染料的光学测绘和荧光发射比率测定法、缺血边界的组织学检查以及包含真实缺血组织电阻和几何结构的心脏组织生物域表示的数学模型来测试这些假设。边界。我们将使用肾上腺素、升高的钾、ATP 依赖性钾通道开放剂 (cromakalim) 和细胞解偶联剂（棕榈油酸）产生全局和区域缺血以及缺血的成分。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早搏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，并将考虑通过细胞解偶联来调节期外收缩诱导。缺血期间电击产生的跨膜电压变化将根据钾升高和 ATP 依赖性钾通道开放的膜电阻调节来考虑。单独的研究将考虑细胞解偶联。通过该项目对缺血期间的期前收缩和除颤机制的了解，将有助于急性心肌缺血后出现心律失常或心源性猝死的患者的诊断和紧急治疗。