Development of transapical MVAD for heart failure therapy

描述（由申请人提供）：本提案旨在完成经心尖小型心室辅助装置（tMVAD）的工程开发和临床前试验，以治疗较不严重的心力衰竭（HF）患者。HF在全球范围内不断增加，在医疗保健资源和成本方面构成了重大负担。尽管医疗保健的进步，HF的预后仍然很差，特别是在晚期。目前，LVAD治疗虽然在增加（4，000例/年），但尚未满足临床需求（> 100，000例HF患者/年）。它需要重大手术干预、心肺转流（CPB）心脏骤停和血液成分暴露，这些都与显著的不良事件发生率和较长的恢复期相关。为了克服这些局限性，HeartWare（迈阿密湖泊，FL）开发了一种小型经心尖左心室辅助装置（tMVAD）。与目前临床试验中的其他MCS器械不同，tMVAD的尺寸和重量明显更小，仅需通过左心室心尖单次插入。tMVAD设计用于流出道的脑室内植入 穿过主动脉瓣的套管。该器械可通过微创入路（肋下切口或小切口）插入左心室心尖，无需创建腹膜前囊袋和吻合流出道移植物。tMVAD由一个基座部分组成，该基座部分连接到左心室附近的心外膜表面 (LV)心尖，将电机驱动电缆从外部输送到LV的竖管，包含tMVAD核心组件和叶片扩散器的泵外壳，以及跨主动脉瓣定位的自定心流出套管。tMVAD的技术优势和临床受益包括顺行血流、无CPB的心脏不停跳手术以及易于植入（和取出），使医生能够治疗较不严重的HF患者，改善患者结局，缩短恢复时间并降低住院费用。在本II期提案中，我们将完成tMVAD的工程开发和临床前测试，以支持FDA提交的I期（n=10）和II期（n=300）临床试验。为实现这一目标，我们将按照人体植入物质量体系的良好生产规范（GMP）规范完成tMVAD的工程开发和设计冻结;通过完成确认和验证（V&V）测试（疲劳）、解剖结构匹配和手术研究，证明tMVAD的有效性和生物相容性（人尸体，n=10），以及在牛模型中的体内急性（n=8）和慢性90天（n=8）研究;并在90天药物非临床研究质量管理规范（GLP）研究中证明了tMVAD在正常（N，n=8）和慢性缺血性心力衰竭（IHF，n=8）动物中的长期安全性和可靠性。GLP研究设计包括对照组（无LVAD支持）与试验组（tMVAD支持）中正常和缺血性心力衰竭牛模型的统计学比较。临床前GLP、V&V和GMP研究数据将用于支持晚期心力衰竭患者临床试验的IDE申请。我们的长期目标是成功地翻译 将HeartWare tMVAD用于临床实践，治疗早期HF患者，以改善患者结局并恢复其生活质量。

DESCRIPTION (provided by applicant): The objective of this proposal is to complete engineering development and pre-clinical testing of a transapical miniaturized ventricular assist device (tMVAD) to treat patients with less advanced heart failure (HF). HF is increasing worldwide and represents a major burden in terms of health care resources and costs. Despite advances in medical care, prognosis with HF remains poor, especially in advanced stages. Currently, LVAD therapy, though increasing (4,000 cases/year), has not yet met the clinical demand (> 100,000 HF patients/yr). It requires a major operative intervention, arrested heart with cardiopulmonary bypass (CPB), and blood component exposure, which have been associated with significant adverse event rates and longer recovery periods. To overcome these limitations, HeartWare (Miami Lakes, FL) has developed a miniaturized transapical left ventricular assist device (tMVAD). Unlike other MCS devices currently in clinical trials, the tMVAD is significantly smaller in size and weight and only requires a single insertion through the apex of the left ventricle. The tMVAD is designed for intraventricular implantation with an outflow cannula that crosses the aortic valve. The device can be inserted via a minimally-invasive approach (subcostal incision or mini-thoracotomy) to access the LV apex, and eliminates the need for creation of the preperitoneal pocket, and anastomosis of the outflow graft. The tMVAD consists of a pedestal section that is attached to the epicardial surface near the left ventricular (LV) apex, a standpipe that carries the drive cables for the motor externally to the LV, a pump housing that contains the tMVAD core assembly and a vane diffuser, and a self-centering outflow cannula positioned across the aortic valve. The technological advantages and clinical benefits of the tMVAD include antegrade flow, beating heart surgery with no CPB, and ease of implant (and removal) that enables physicians to treat patients with less advanced HF, improve patient outcomes shorten recovery time, and lower hospital costs. In this phase II proposal, we will complete engineering development and pre-clinical testing of the tMVAD to support a FDA submission for phase one (n=10) and phase two (n=300) clinical trials. To achieve this objective, we will complete the engineering development and design freeze of the tMVAD in compliance with Good Manufacturing Practices (GMP) specifications for a human implant quality system; demonstrate efficacy and biocompatability of the tMVAD by completing Validation and Verification (V&V) testing (fatigue), anatomical fit and surgical procedure study (human cadaver, n=10), and in vivo acute (n=8) and chronic 90- day (n=8) studies in a bovine model; and demonstrate long-term safety and reliability of the tMVAD in normal (N, n=8) and chronic ischemic heart failure (IHF, n=8) animals in a 90-day Good Laboratory Practices (GLP) study. The GLP study design includes statistical comparison of normal and ischemic heart failure bovine model in control (no LVAD support) to test (tMVAD support) groups. The pre-clinical GLP, V&V, and GMP study data will be used to support an IDE application for a clinical trial in patients with advanced heart failure. Our long- term goal is to successfully translate the HeartWare tMVAD into clinical practice to treat earlier stage HF patients to achieve improved patient outcomes and restore their quality of life.