Left Atrial Appendage Inversion to Prevent Stroke

摘要 心房纤颤（AF）是最常见的心律失常，影响1-2%的人口，约8%的人患有心房纤颤。 80岁以上的人。AF已被确定为血栓栓塞事件的主要原因，例如 中风在美国，每小时约有15名AF患者发生中风。虽然预防 心源性卒中在临床上和经济上都很严重，传统的口服抗凝治疗没有 沿着而来的是许多缺点。据估计，超过90%的血栓 由于左心耳（LAA）心尖狭窄（盲），导致房颤形式的血栓栓塞事件 内表面不光滑，收缩不规则。使用器械切除或隔绝左心耳， 预防房颤患者血栓栓塞事件的新治疗策略。有两种类型的设备; 也就是说，心外膜缝线/夹子，从心脏外部闭合LAA，以及心内展开的封堵器， 从内部消除了死区当前的装置具有一些显著的缺点， 然而，如成本高，异物滞留，迁移等，心外膜装置似乎达到更好的 结果比内支架器械更好，但心外膜入路更难进入。在第一阶段的概念验证中， 该提案的目的是部分倒置LAA腔内，使其随着时间的推移再吸收。这是两全其美 World方法（通过腔内方法进行夹闭或吸收的有效性）应优于上级 现有的设备和方法。假设左心耳的倒置会改变应力分布 （内稳态）在附件中通过减少拉伸应力，甚至产生一些压缩应力， 根据生长-应力定律，应力或压缩的减少将导致吸收的组织。主要 可交付成果是通过EKG、超声心动图、组织学 心脏生物标志物和神经激素，以建立与LAA相反的LAA再吸收新范例 封闭或排斥。我们的初步数据显示了这种方法在猪模型中的可行性， 通过手术和血管内实现左心耳内翻，发现可消除左心耳死腔。在 在猪的开胸手术中，我们在术后4周进行了测量，显示了倒置 LAA的安全性（无心律失常，无血流动力学或心脏变化）和有效性（LAA被再吸收）。相比 对于目前的LAA闭合装置，我们的方法没有留下任何东西（即，无植入器械），因此将 更安全，更便宜。这一创新理念沿着经皮穿刺方法的发展 为此目的，不仅将提供一种预防AF相关栓塞事件的新治疗方法， 减少中风的人类、社会和经济负担。

ABSTRACT Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 1-2% of the population, and about 8% of individuals over 80 years of age. AF has been identified as the leading cause of thromboembolic events such as stroke. Every hour, approximately 15 patients with AF will suffer from a stroke in the US. Although prevention of cardioembolic stroke is clinically and economically critical, traditional oral anticoagulation therapy does not have satisfactory compliance, along with number of drawbacks. It is estimated that more than 90% of thrombi responsible for thromboembolic events in AF form in the left atrial appendage (LAA) due to its narrow apex (blind end), unsmooth inner surface, and irregular contraction. Excision or exclusion of the LAA with devices provides a novel treatment strategy for preventing thromboembolic events in AF patients. There are two types of devices; i.e., epicardial suture/clip, which closes the LAA from outside the heart, and endocardially deployed occluder, which eliminates the dead space from the inside. The current devices have some significant disadvantages, however, such as high cost, foreign body retention, migration, etc. The epicardial device seems to achieve better results than endocardial device but the epicardial approach is harder to access. In this Phase I proof of concept proposal, the objective is to partially invert the LAA endoluminally to make it resorb over time. This best of both world approach (efficacy of clipping or resorption through an endoluminal approach) should be superior to existing devices and methods. The hypothesis is that the inversion of the LAA will change the stress distribution (homeostasis) in the appendage by reducing the tensile stress and even create some compressive stresses in the tissue where a reduction in stress or compression will cause resorption as per growth-stress law. The major deliverable is to demonstrate the safety of LAA inversion as assessed by EKG, echocardiography, histology, cardiac biomarkers, and neurohormones to establish a new paradigm of LAA resorption as opposed to LAA occlusion or exclusion. Our preliminary data show feasibility of this approach in a swine model where the partial inversion of LAA was implemented surgically and endovascularly and found to eliminate the LAA dead space. In the open-chest procedure in swine, we performed measurements at 4 weeks post-surgery, showing the inversion of LAA is safe (no arrythmia, no hemodynamic or cardiac changes) and effective (LAA was resorbed). Compared to current LAA closure devices, our approach leaves nothing behind (i.e., no implanted device) and hence will be safer and much less expensive. This innovative concept along with the development of percutaneous method for this purpose will not only provide a new treatment for the prevention of AF related embolic events but also reduce human, social and economic burden of stroke.