ELECTRICAL RESTITUTION AND VENTRICULAR FIBRILLATION

描述（根据申请人的描述改编）： 心室纤维性颤动（VF）仍然知之甚少。当前 一个公认的观点是VF的发作涉及到一个单一的 螺旋波变成许多自我延续的波，这样一个过程需要 动作电位之间恢复关系的斜率 持续时间（APD）及其先前舒张间期等于或大于 1.同样的理论预计，一个单一的螺旋波将是稳定的（不 分解），如果APD恢复关系的斜率小于1。 使用新的动态测量协议，研究人员已经表明， 犬APD恢复关系的斜率等于或大于1 钙通道阻滞剂和高钾血症可降低 正常三维空间中恢复关系与VF抑制 心肌现在提出了三个目标（实际上是假设）。1)增加 复极化钾电流也降低了APD恢复关系的斜率 并抑制VF。这将通过使用Luo-Rudy 膜模型和耦合LRD型元件的2-D表，以及通过 增加复极化钾电流的实验干预。假设2） 指出APD恢复关系斜率的减小也 在急性心肌梗死的情况下抑制VF。为了验证这一 假设，APD和传导速度的恢复关系将是 在灌注的犬心室和完整的 Langendorff灌注犬心脏，以及缺血对 将确定VF的诱导和维持。减少的干预措施 APD恢复关系的斜率将被传递以确定 是否能将心室颤动转化为周期性节律假设3）VF 也可以在二维心肌中诱导， APD恢复关系斜率的改变。为了解决这个问题， 传导速度和APD的恢复关系将在 犬和马的心外膜，切除大 2-心外膜组织的三维薄片。将尝试诱导VF 使用快速起搏，每次尝试的成功或失败将 与APD恢复关系的斜率相关。如果诱发VF， 已知可降低APD斜率的干预措施对VF的影响 将确定恢复关系。这些研究将有助于确定 APD恢复动力学在VF发展中的相对作用，与 其他已知或疑似VF调节剂，在正常和缺血性 心肌减小APD恢复关系斜率的新策略 从而抑制VF可能提示新的药物治疗方法， 预防VF和心源性猝死。

DESCRIPTION (adapted from the applicant's description): The mechanism for ventricular fibrillation (VF) is still poorly understood. The currently accepted notion is that the onset of VF involves the disintegration of a single spiral wave into many self-perpetuating waves and that such a process requires that the slope of the restitution relation between the action potential duration (APD) and its previous diastolic interval is equal to or greater than 1. The same theory anticipates that a single spiral wave will be stable (not disintegrate) if the slope of the APD restitution relation is less than 1. Using a new dynamic measurement protocol, the investigators have shown that the slope of the APD restitution relation is equal to or greater than 1 in canine endocardium, and that Ca channel blockers and hyperkalemia reduce the slope of the restitution relation and suppress VF in normal three-dimensional myocardium. Three aims (in reality, hypotheses) are now proposed. 1) Increasing repolarizing K currents also reduces the slope of the APD restitution relation and suppresses VF. This is to be tested via simulation using the Luo-Rudy membrane model and 2-D sheets of coupled LRd-type elements, and via experimental interventions that increase repolarizing K currents. Hypothesis 2) states that reductions in the slope of the APD restitution relation also suppress VF in the setting of acute myocardial infarction. To test this hypothesis, restitution relations for both APD and conduction velocity will be determined during ischemia in perfused canine ventricle and in intact Langendorff-perfused canine hearts, and the effects of ischemia on the induction and maintenance of VF will be determined. Interventions that reduce the slope of the APD restitution relation will then be delivered to determine whether they convert the VF into a periodic rhythm. Hypothesis 3) is that VF can also be induced in two-dimensional myocardium and can be modulated by alterations in the slope of the APD restitution relation. To address this, the restitution relations for conduction velocity and APD will be determined in canine and equine epicardium, prior to and after excision of large 2-dimensional sheets of epicardial tissue. Attempts will be made to induce VF using rapid pacing and the success or failure of each attempt will be correlated with the slope of the APD restitution relation. If VF is induced, the effects on the VF of interventions known to reduce the slope of the APD restitution relation will be determined. These studies will help to define the relative role of APD restitution kinetics in the development of VF, vis-a-vis other known or suspected modulators of VF, in both normal and ischemic myocardium. New strategies to reduce the slope of the APD restitution relation and thereby suppress VF may suggest novel pharmacological therapies for the prevention of VF and sudden cardiac death.