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.

本修订申请的目的是研究细胞内Ca（Cai）动力学与室颤（VF）和除颤机制之间的关系。在目前的资助期内，我们发现Cai动力学和自发舒张肌浆网（SR）Ca释放对初始除颤成功或失败很重要。Cai动力学是否在初次成功除颤后的复发性自发性VF中起作用尚不清楚。已知自发性VF发作在心肺复苏期间和VF风暴患者中频繁发生。SR韦恩Chen实验室的初步研究表明，钙超载诱导的钙释放（SOICR）是SR自发钙释放的重要机制。他们还发现，卡维地洛及其类似物（VK-II-36）可有效降低大鼠心室肌细胞2型兰尼碱受体（RyR 2）对腔钙的敏感性，抑制SR钙释放。这些发现表明，抑制SOICR可能提供一种新的方法，以提高除颤效率和预防休克后自发性VF。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也可能在衰竭和缺血性心脏的休克后心律失常中发挥作用。晚期3相EAD的发生是因为动作电位时程（APD）缩短和持续升高的Cai共存。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是休克后心律失常的重要机制，则单独抑制SOICR可能无法在休克后阶段达到抗心律失常作用。我们推测：（1）自发性（非电压门控）SR Ca释放和晚期3相EAD都是发生休克后心律失常的重要机制;（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SVF的复发。我们将在兔心室内膜上进行Cai和膜电位（Vm）的双重光学标测，以记录SOICR诱导的正常心室和缺血心室的延迟后去极化。我们还将研究VK-II-36（SOICR抑制剂）对休克后心律失常的影响。这些研究将为我们提供新的见解VF和除颤的机制，并帮助测试的假设，抑制SOICR是一种新的方法来控制心律失常。