Device for Treatment of Cardiac No-Option Patients

摘要 在每年近100万的美国心肌梗死患者中，15-20%的人是不良候选人 由于弥漫性CAD、多个支架和失败的CABG而进行CABG或PCI，因此被认为是“无- 选择”患者。这些患者每天遭受严重的心绞痛、呼吸短促、疲劳等， 冠状动脉旁路移植术或经皮冠状动脉介入治疗（PCI）通常无法治疗，在这些情况下， 条件如果没有心脏移植，没有选择的患者通常会发展为CHF。公司 该技术能够为没有选择的患者提供不依赖于修复动脉的血运重建治疗 系统该疗法是一种分阶段的方法，使用一种新型的静脉压力预处理（VPP）装置， 通过冠状静脉旁路移植术（CVBG）预充冠状静脉进行逆向灌注。VPP的发展 该装置专注于克服与冠状动脉逆向灌注相关的局限性， 灌注压突然升高，导致心肌水肿和出血。我们的方法 避免了冠状静脉中的压力从静脉（10-20 mmHg）急剧升高到动脉值（100-120 mmHg），而是在中间水平（动脉和静脉之间）调节压力 水平）。重要的是，我们的I期研究结果表明，左心室的动脉化是安全和选择性的。 前降支冠状静脉使用经皮输送VPP器械。这个概念验证是 表现为较厚的血管壁和较大程度的功能性平滑肌细胞（即，应对 药物激动剂和拮抗剂）在VPP器械闭塞的预处理血管中的作用， 正常的静脉。我们以前的研究已经证明，这种程度的重塑静脉安全地使 在全动脉压下反向灌注，无水肿或出血。为了推进这些杰出的发现， 慢性逆向灌注治疗方法必须在临床相关条件下受到挑战， 类似于“无选择”患者的多种合并症。因此，第二阶段的提案推动了这一点， 有前途的技术在两个特定的目标：1）证明慢性逆向灌注的功效，使之成为可能， VPP器械在DCAD和局灶性缺血共病转化动物模型中的慢性动物研究; 和2）在慢性动物研究中收集GLP安全性数据，以向FDA提交IDE。这项II期 研究提出了为“无选择”患者提供血运重建的高度重要的临床需求， 在各个国家卫生研究院和中心的影响。

ABSTRACT Of the nearly 1 million US patients suffering from myocardial infarction each year, 15-20% are poor candidates for CABG or PCI because of diffuse CAD, multiple stents, and failed CABG and are therefore considered "no- option" patients. These patients suffer daily from severe angina, shortness of breath, fatigue, and the like and are frequently untreatable by CABG or PCI which has been shown to have very poor outcomes under these conditions. Without a heart transplant, the no-option patient typically progresses to CHF. The Company’s technology enables a revascularization therapy for the no-option patient that is not reliant on repairing the arterial system. The therapy is a staged approach which uses a novel venous pressure preconditioning (VPP) device to prime the coronary vein for retroperfusion via coronary vein bypass graft (CVBG). Development of the VPP device has focused on overcoming limitations associated with coronary retroperfusion that have stemmed from abrupt increases in perfusion pressure, leading to edema and hemorrhage of the myocardium. Our approach avoids acutely raising the pressure in the coronary veins from venous (10-20 mmHg) to arterial values (100-120 mmHg) in a single step and instead, regulates the pressure at an intermediate level (between arterial and venous levels). Importantly, results from our Phase I studies have shown safe and selective pre-arterialization of the left anterior descending coronary vein using the percutaneously delivered VPP devices. This proof-of-concept was demonstrated by thicker vessel walls and with greater degree of functional smooth muscle cells (i.e., respond to pharmacological agonist and antagonist) in the preconditioned vessels occluded by the VPP device compared to normal veins. Our previous studies have demonstrated that veins with this degree of remodeling safely enable retroperfusion at full arterial pressure without edema or hemorrhage. To advance these outstanding findings, the chronic retroperfusion therapeutic approach must be challenged under clinically relevant conditions that resemble the multiple comorbidities of “no-option” patients. Accordingly, this Phase II proposal advances this promising technology in two specific aims: 1) To demonstrate efficacy of chronic retroperfusion enabled by the VPP device in a chronic animal study of a translational animal model of DCAD and focal ischemia comorbidities; and 2) To collect GLP safety data in a chronic animal study for an IDE submission to the FDA. This Phase II study addresses a highly significant clinical need for providing revascularization for “no-option” patients and can reach across various NIH Institutes and Centers.