Fibrillation and Defibrillation

此修订应用的目的是研究细胞内钙(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，我们发现CAI动力学和舒张期肌浆网(SR)的自发钙释放对初始除颤的成败起着重要的作用。CAI动力学在初始成功除颤后复发的自发性室颤中是否起作用尚不清楚。众所周知，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。来自SR Wayne Chen实验室的初步研究表明，储存超载诱导的钙释放(SOICR)是自发性SR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)可以有效地降低大鼠心室肌细胞2型兰尼定受体(RyR2)对鲁米诺钙的敏感性，并抑制SR钙的释放。这些结果表明，抑制SOICR可能为改善除颤效果和预防休克后自发性室颤提供了一种新的途径。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相EAD也可能在衰竭和缺血心脏的休克后心律失常中发挥作用。晚期3EAD的发生是由于动作电位时程缩短和持续升高的CaI并存。这种CaI升高是由钙诱导的钙释放引起的，而不是由SOICR引起的。如果晚期3EAD是休克后心律失常的重要机制，那么单靠抑制SOICR在休克后阶段可能不能达到抗心律失常的效果。我们推测：(1)自发性(非电压门控)SRCa释放和晚期3EAD均是休克后心律失常发生的重要机制；(2)抑制SOICR可提高除颤初期疗效，预防除颤成功后的SVF复发。我们将在兔的心室内膜上进行CAI和膜电位(Vm)的双重光学标测，以证明SOICR在正常和缺血室引起的延迟后除极。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室颤和除颤机制的新见解，并有助于验证抑制SOICR是控制心律失常的新方法的假设。

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.