Mechanisms of Arrhythmias and Defibrillation in Ischemia

缺血时心律失常和除颤的机制

• 批准号: 6792065
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6792065
• 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.

缺血会导致心律失常，并可能提高除颤阈值。为了提高对缺血患者的了解和治疗，需要了解缺血期间心律失常和除颤阈值变化的机制。本项目将验证以下假设：1)局部缺血边缘的跨膜电位梯度和曲率导致早搏；2)缺血减少电击引起的跨膜电压变化。我们将在分离的心脏和心肌细胞培养中使用电压敏感染料的光学映射和荧光发射比率法、缺血边界的组织学检查以及包含真实缺血组织阻力和边界几何形状的心脏组织的生物域表示的数学建模来验证这些假设。我们将用肾上腺素、升高的钾、依赖于ATP的钾通道开放剂(克罗卡林)和细胞解偶联剂(棕榈油酸)来产生全局和局部缺血以及部分缺血。我们将通过测量跨心外膜和心内膜缺血或高钾交界处跨膜电位的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一个重要变量，并将考虑细胞解偶联对早搏诱导的调制。缺血期间电击引起的跨膜电压变化将从钾升高和ATP依赖的钾通道开放引起的膜电阻调制的角度来考虑。单独的研究将考虑细胞解偶联。通过本项目对缺血期间早搏和除颤机制的了解，将有助于急性心肌缺血后不久发生心律失常或心脏性猝死的患者的诊断和急救。