Fibrillation and Defibrillation

颤动和除颤

• 批准号: 7741761
• 负责人: PENG-SHENG CHEN
• 金额: $ 38.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741761
• 关键词: Action Potentials; Arrhythmia; Calcium; Cardiopulmonary Resuscitation; Country; Development; Electric Countershock; Endocardium; Failure; Funding; Goals; Ischemia; Laboratory Study; Maps; Membrane Potentials; Muscle Cells; Myocardial Ischemia; Optics; Oryctolagus cuniculus; Patients; Phase; Play; Preparation; Public Health; Rattus; Recurrence; Role; RyR2; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Testing; Ventricular; Ventricular Fibrillation; analog; carvedilol; improved; inhibitor/antagonist; insight; novel strategies; prevent; success; sudden cardiac death; voltage

The goal of this revised application is to study the relationships between intracellular Ca (Cai) dynamics and the mechanisms of ventricular fibrillation (VF) and defibrillation. In the present funding period, we discovered that Cai dynamics and spontaneous diastolic sarcoplasmic reticulum (SR) Ca release are important to the initial defibrillation success or failure. Whether or not Cai dynamics play a role in the recurrent spontaneous VF after initial successful defibrillation remains unclear. Spontaneous VF episodes are known to occur frequently during cardiopulmonary resuscitation and in patients with VF storms. Preliminary studies from the laboratory of SR Wayne Chen suggested that store overload induced Ca release (SOICR) is an important mechanism of spontaneous SR Ca release. They also found that carvedilol and its analog (VK-II-36) can effectively reduce the sensitivity of type 2 ryanodine receptor (RyR2) to luminal Ca and suppress SR Ca release in rat ventricular myocytes. These findings suggest that inhibition of SOICR may provide a novel approach to improve defibrillation efficacy and prevent postshock spontaneous VF. However, SOICR may not be the only mechanism for postshock arrhythmias. Our preliminary studies showed that late phase 3 EAD may also play a role in postshock arrhythmias in failing and ischemic hearts. The late phase 3 EAD occurs because of the coexistence of shortened action potential duration (APD) and persistently elevated Cai. This Cai elevation is induced by Ca induced Ca release, not SOICR. If late phase 3 EAD is an important mechanism for postshock arrhythmias, then SOICR inhibition alone may not achieve antiarrhythmic effects in the postshock period. We hypothesize that (1) Spontaneous (non-voltage gated) SR Ca release and late phase 3 EAD are both important mechanisms for the development of the postshock arrhythmias and (2) Inhibition of SOICR can improve initial efficacy of ventricular defibrillation and prevent recurrent SVF after successful defibrillation attempts. We will perform dual optical mapping of Cai and membrane potential (Vm) on rabbit ventricular endocardium to document SOICR-induced delayed after depolarization in normal ventricles and in ischemic ventricles. We will also study the effects of VK-II-36, a SOICR inhibitor, on postshock arrhythmias. These studies will provide us new insights into the mechanisms of VF and defibrillation, and help test the hypothesis that inhibition of SOICR is a novel approach to arrhythmia control.

此修订应用程序的目标是研究细胞内 Ca (Cai) 动力学与心室颤动 (VF) 和除颤机制之间的关系。在目前的资助期间，我们发现Cai动力学和自发舒张肌浆网（SR）Ca释放对于初始除颤的成功或失败很重要。蔡动力学是否在初次成功除颤后复发的自发性室颤中发挥作用仍不清楚。据了解，自发性室颤发作在心肺复苏期间和室颤风暴患者中经常发生。 SR Wayne Chen 实验室的初步研究表明，储存超载诱导的 Ca 释放（SOICR）是自发 SR Ca 释放的重要机制。他们还发现卡维地洛及其类似物（VK-II-36）可以有效降低2型兰尼碱受体（RyR2）对管腔Ca的敏感性，并抑制大鼠心室肌细胞中SR Ca的释放。这些发现表明，抑制 SOICR 可能提供一种提高除颤效果和预防电击后自发性心室颤动的新方法。然而，SOICR 可能不是休克后心律失常的唯一机制。我们的初步研究表明，晚期 3 期 EAD 也可能在心脏衰竭和缺血性休克后心律失常中发挥作用。晚期 3 期 EAD 的发生是由于动作电位持续时间 (APD) 缩短和 Cai 持续升高并存。这种 Cai 升高是由 Ca 诱导的 Ca 释放引起的，而不是 SOICR。如果晚期 3 期 EAD 是电击后心律失常的重要机制，那么单独抑制 SOICR 可能无法在电击后阶段达到抗心律失常作用。我们假设 (1) 自发（非电压门控）SR Ca 释放和晚期 3 期 EAD 都是电击后心律失常发生的重要机制；(2) 抑制 SOICR 可以提高心室除颤的初始疗效，并防止成功除颤后复发 SVF。我们将对兔心室心内膜进行 Cai 和膜电位 (Vm) 的双重光学测绘，以记录 SOICR 诱导的正常心室和缺血性心室除极后延迟。我们还将研究 SOICR 抑制剂 VK-II-36 对休克后心律失常的影响。这些研究将为我们提供对 VF 和除颤机制的新见解，并有助于检验抑制 SOICR 是一种控制心律失常的新方法这一假设。