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.

此修订应用的目的是研究细胞内CA（CAI）动力学与心室纤颤（VF）和除颤之间的关系。在目前的资金期间，我们发现CAI动力学和自发性舒张性肌浆网（SR）CA释放对初始除颤成功或失败至关重要。最初成功的除颤后，CAI动力学是否在反复的自发VF中起作用，尚不清楚。已知自发的VF发作经常发生在心肺复苏期间和VF风暴患者中。 SR Wayne Chen实验室的初步研究表明，商店过载诱导的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）可以有效地降低2型ryanodine受体（RYR2）对腔内CA的敏感性，并抑制大鼠心室肌细胞中的SR CA释放。这些发现表明，对SOICR的抑制可能会提供一种新的方法来提高除颤功效并防止后震后自发VF。但是，SOICR可能不是震后心律不齐的唯一机制。我们的初步研究表明，第3阶段EAD也可能在失败和缺血性心脏中的震后心律不齐中发挥作用。第3阶段EAD之后是由于缩短的动作电位持续时间（APD）并持续升高的CAI的共存。 CA诱导的Ca释放而不是SOICR诱导了这种CAI升高。如果后期3期EAD是震后心律不齐的重要机制，则单独的SOICR抑制作用可能无法在震后时期实现抗心律失常效应。我们假设（1）自发性（非电压门控）SR CA释放和后期第3阶段EAD都是发展后震动心律不齐的重要机制，并且（2）抑制SOICR可以提高心室脱激的初始功效，并在成功的除颤尝试后，可预防经常出现的SVF。我们将对兔心室心内膜心脏的CAI和膜电位（VM）进行双重光学映射，以记录在正常心室和缺血性心室中去极化后SOICR诱导的延迟。我们还将研究SOICR抑制剂VK-II-36对震后心律不齐的影响。这些研究将为我们提供有关VF和除颤机制的新见解，并有助于检验以下假设：抑制SOICR是一种心律不齐的新方法。