Translating post-infarct ventricular tachycardia mechanisms into a therapy

摘要 在美国，每年有数十万人经历心脏骤停， 大多数人死于这种情况。大约三分之二的心脏骤停患者以前曾遭受过 心肌梗死(MI)和死亡是由对心肌梗死愈合的不良适应反应造成的。痊愈的脑梗塞 疤痕会产生一种支持恶性室性心律失常的底物，而死亡是由室性心律失常引起的。 起源于梗死疤痕周围交界区的心动过速。盛行的范式侧重于 心肌组织存活带穿越交界区和电功能受损的作用 传导作为心律失常机制的组成部分。将室性心动过速的原因完全归因于 这些导电因素是它们弥漫地出现在整个边界地带，但室速存在于 分立电路。我们最近报道了钾通道β亚基KCNE3和KCNE4是 仅在室速回路中上调，并且这些蛋白质引起一种复极异质性模式， 支持可重入VT。我们还表明，基因转移的复极延长或传导 加强转基因可降低或消除室性心动过速的诱发性。我们之前开发出了一种心外膜基因 涂抹方法进行跨壁心房基因转移，我们有初步数据表明使用 用腺相关病毒载体绘制心外膜基因可获得完整的跨室壁基因 调职。在这项提案中，我们利用这些发现来开发一种治疗梗塞后室性心动过速的方法。我们假设 VT电路特有的复极化效应与更广泛存在的传导变化相结合 创造一个有利于VT再入的环境，使复极化和/或传导正常化将 预防VT。为了验证我们的假设，我们将集中在三个目标上：(1)使治愈的心肌梗塞的复极均质化 SCAR；(2)通过增加间盘蛋白的表达使传导速度和细胞连接正常化。 连接蛋白43；(3)评估拟议干预措施的安全性和生物分布。成功完成 这些目标将创建一个临床前数据包，以支持未来VT基因治疗的临床测试。

ABSTRACT In the United States, several hundred thousand people experience cardiac arrest each year, with the vast majority dying from this condition. Approximately two-thirds of cardiac arrest victims have previously suffered a myocardial infarction (MI), and death results from maladaptive responses to infarct healing. The healed infarct scar creates a substrate that supports malignant ventricular arrhythmias, and death results from ventricular tachycardia (VT) originating in the border zone around the infarct scar. The prevailing paradigm focused on the role of surviving ribbons of myocardial tissue traversing the borderzone region and impaired electrical conduction as components of the arrhythmia mechanism. A problem with ascribing causation of VT entirely to those electrical conduction factors is that they occur diffusely throughout the borderzone, but VT exists in discrete circuits. We recently reported that the potassium channel beta subunits KCNE3 and KCNE4 are upregulated only in VT circuits, and that these proteins cause a pattern of repolarization heterogeneity that supports reentrant VT. We have also shown that gene transfer of either repolarization prolonging or conduction enhancing transgenes reduces or eliminates VT inducibility. We previously developed an epicardial gene painting method for transmural atrial gene transfer, and we have preliminary data showing that use of epicardial gene painting with adeno-associated virus vectors allows complete transmural ventricular gene transfer. In this proposal, we exploit these findings to develop a cure for post-infarct VT. We hypothesize that the VT circuit-specific repolarization effects combine with the more broadly present alterations in conduction to create an environment conducive for reentry VT, and that normalizing repolarization and/or conduction will prevent VT. To test our hypothesis, we will focus on 3 aims: (1) to homogenize repolarization in healed MI scar; (2) to normalize conduction velocity and cellular connectivity by increasing intercalated disk expression of connexin43; (3) to evaluate safety and biodistribution of the proposed interventions. Successful completion of these aims will create a preclinical data package required to support future clinical testing of VT gene therapy.