ELECTRICAL RESTITUTION AND VENTRICULAR FIBRILLATION

描述(改编自申请人的描述)： 室颤(VF)目前仍知之甚少。目前的 公认的观点是室颤的发生涉及单个 螺旋波变成许多自我永续的波，这样的过程需要 动作电位之间恢复关系的斜率 持续时间(Apd)及其先前的舒张期间期等于或大于 1.同样的理论认为，单个螺旋波将是稳定的(而不是 解体)，如果apd恢复关系的斜率小于1。 使用一种新的动态测量方案，研究人员已经证明 犬的动作电位恢复关系斜率等于或大于1 心内膜，钙通道阻滞剂和高钾血症可降低 正常三维中的恢复关系和抑制VF 心肌。现在提出了三个目标(实际上是假设)。1)增加 K电流的重新极化也降低了动作电位恢复关系的斜率 并抑制VF。这将通过使用Luo-Rudy的模拟进行测试 膜模型和LRD型耦合单元的二维片，以及过孔 增加复极K电流的实验干预。假设2) 声明说，减少警察局恢复原状的斜率也 在急性心肌梗塞时抑制室性心动过速。为了测试这一点 假设，apd和传导速度的恢复关系将是 犬全心和全心缺血时的测定 Langendorff灌流的犬心，以及缺血对心脏的影响 VF的诱导和维持将被确定。减少的干预措施 然后，将会提供apd恢复关系的斜率，以确定 是否将VF转换为周期节律。假设3)是VF 也可以在二维心肌中诱导，并可以通过 警方恢复原状关系斜率的变化。为了解决这个问题， 传导速度和apd的恢复关系将在中确定。 犬和马心外膜切除前后的大面积 心外膜组织的二维薄片。将尝试诱发室颤 使用快速起搏和每一次尝试的成功或失败 与动作电位恢复关系的斜率相关。如果室颤被诱发， 已知可降低动作电位时程斜率的干预措施对室性心动过速的影响 将确定恢复原状的关系。这些研究将有助于定义 动作电位恢复动力学在室性心动过速发展中的相对作用 其他已知或可疑的室性心动过速调节器，在正常和缺血状态下 心肌。减少APD恢复关系斜率的新策略 从而抑制室性心动过速可能会提示新的药物治疗 预防室颤和心源性猝死。

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.