Mechanisms of Arrhythmias and Defibrillation in Ischemia

缺血时心律失常和除颤的机制

• 批准号: 6656373
• 负责人: STEPHEN B KNISLEY
• 金额: $ 19.86万
• 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/6656373
• 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.

缺血引入心律不齐，并可能增加除颤阈值。为了提高缺血患者的理解和治疗，需要在缺血期间对心律不齐的机制以及除颤阈值变化的了解。该项目将检验以下假设：1）区域缺血边界的跨膜电位和曲率的梯度诱导外石，2）缺血减少电击产生的跨膜电压变化。我们将使用孤立心脏和心肌培养物中的电敏染料的光学映射和荧光发射比计测试这些假设，对缺血边界的组织学检查以及具有含有逼真的缺血性组织阻力和边界的含量的心脏组织的生物域表示的数学建模。我们将与肾上腺素，钾，依赖ATP依赖的钾通道开瓶器（Cromakalim）和细胞解偶联剂（棕榈酸）（棕榈酸）产生全球缺血和缺血成分。我们将通过测量跨膜或高钾血症边界的跨膜电位的梯度在表心和心内心脏的脑膜边界上测量跨膜电位的梯度来确定外部高血症和缺血的依赖性。研究将强调边界曲率是聚焦损伤电流的重要变量，并将考虑通过细胞解偶偶联来调节螺栓诱导。跨膜电压在缺血期间通过电击产生的变化将通过升高钾和ATP依赖性钾通道的开口来考虑膜电阻调节。单独的研究将考虑细胞解偶联。从该项目中获得的缺血期间，对外沟和除颤机制的理解将有助于诊断和紧急治疗急性心肌缺血后不久发生心律不齐或心脏猝死的患者。