GOALI: Model and Experimental Studies of the Evolution of the Excitable Gap for Improved Anti-Tachycardia Pacing

9903466 Pollard将植入式心律转复除颤器（ICD）引入心肌梗死（MI）幸存患者体内，形成了每年20亿美元的产业。因此，人们对提高ICD管理危及生命的心律失常的能力非常感兴趣。ICD感测心率，并且在适当的情况下，它们或者递送高能量除颤电击以抑制心脏的电活动，或者递送低能量抗心动过速起搏（ATP）刺激序列。由于ATP避免了电击的需要，因此电池耗尽和电击引起的疼痛都被最小化。虽然ATP可以是高度有效的，但是个体刺激必须在心律失常的可兴奋间隙期间施加，此时邻近起搏电极的组织已经有足够的时间从前一周期恢复兴奋性，但是在当前周期中尚未被兴奋。因此，对可兴奋间隙在具有可变复杂性的心律失常期间如何演变的基本理解将有利于改善ATP，因为该理解可用于确保可兴奋间隙中的起搏。我们假设ATP功效的改善与刺激：（i）发生在早期，接近心律失常的发作，当兴奋间隙相对较大时;（ii）来自多个部位，增加了可兴奋组织被捕获的可能性。虽然ICD的心率感知能力的改善可以促进早期ATP，并且左侧电极导线的引入可以促进多部位ATP，但在这些方法被普遍接受之前，显然需要证明改善的疗效。我们将：（1）开发一种数值方法来估计心律失常底物的复杂性增加的可兴奋间隙的演变。将在综合模拟中评估可兴奋间隙，这将允许在心律失常可重复的设置中仔细确定MI的几何特性与心律失常形成之间的关系;（2）开发一种实验方法来测量日益复杂的心律失常基质的可兴奋间隙的演变。将在家兔冷冻损伤模型中通过程控起搏进行心律失常诱导，在该模型中，对内膜和中层心肌进行快速冷冻消融，并在心外膜引入解剖障碍（简单基质），采用冷冻消融内膜的48小时MI模型（中等复杂性）和48小时MI模型（真实基质）。我们将绘制这些心律失常基质中的可兴奋间隙，以记录其在室性心动过速（VT）期间的演变;（3）量化复杂性增加的基质中的早期、晚期、单部位和多部位ATP疗效。使用计算机模拟和动物实验，这种量化将允许测试我们的主要假设。这个产学合作项目将由一个研究小组执行，该研究小组由伯明翰亚拉巴马大学的学术科学家和Guidant公司的工业科学家组成，Cardiac Pacemakers，Inc.

9903466PollardThe introduction of implantable cardioverter defibrillators (ICDs) into patients surviving myocardial infarction (MI) makes up a $2 billion per year industry. As a result, there is considerable interest in improving ICDs' ability to manage life-threatening arrhythmias. ICDs sense heart rate, and when appropriate they either deliver a high-energy defibrillation shock to resynchronize the heart's electrical activity or they deliver trains of low-energy anti-tachycardia pacing (ATP) stimuli. Since ATP obviates the need for shocks, battery depletion and pain from the shock are both minimized. While ATP can be highly effective, the individual stimuli must be applied during the arrhythmia's excitable gap, when tissue adjacent to the pacing electrode has had sufficient time to recover excitability from the preceding cycle but has not yet been excited in the present cycle. A basic understanding of how the excitable gap evolves during arrhythmias with variable complexity would therefore be advantageous for improved ATP because that understanding could be used to insure pacing in the excitable gap. We hypothesize improved ATP efficacy with stimuli that: (i) occur early, near the onset of the arrhythmia, when the excitable gap is relatively large; and (ii) come from multiple sites, increasing the likelihood that excitable tissue can be captured. While improved rate sensing capabilities of ICDs can facilitate early ATP and the introduction of left-sided leads can facilitate multiple site ATP, there is a clear need to demonstrate improved efficacy before such approaches become generally accepted. We will: (1) develop a numerical approach to estimate the evolution of the excitable gap for arrhythmia substrates of increasing complexity. Excitable gap will be assessed in comprehensive simulations that will allow careful determination of the relationship between the MIs' geometric properties and arrhythmia formation in a setting where the arrhythmias will be undeniably repeatable; (2) develop an experimental approach to measure the evolution of the excitable gap for arrhythmia substrates of increasing complexity. Arrhythmia induction by programmed pacing will be performed in a rabbit freeze lesion model in which the endocardium and mid-myocardium are rapidly cryoablated and an anatomic obstacle is introduced epicardially (simple substrate), a 48h MI model with cryoablated endocardium (intermediate complexity), and a 48h MI model (realistic substrate). We will map the excitable gap in these arrhythmia substrates to document its evolution during ventricular tachycardia (VT); and (3) quantify early, late, single site and multiple site ATP efficacy in substrates of increasing complexity. Using the computer simulations and the animal experiments, such quantification will allow tests of our main hypotheses. This Industry-University Collaborative project will be performed by a research team made up of academic scientists from the University of Alabama at Birmingham and industry scientists from Guidant Corp., Cardiac Pacemakers, Inc.