Continuous Flow Ventricular Assist Device-Induced Platelet Dysfunction

充血性心力衰竭（CHF）在西方世界是一种日益严重的流行病，在美国有550万人受到影响，每年诊断出另外55万新患者。即使医疗器械、急性冠状动脉介入治疗和手术技术得到改善，CHF的1年和5年死亡率仍为10%和80%，在过去20年中几乎没有变化。唯一确定的治疗方法是心脏移植，但这仍然受到数量（每年可提供2，200个供体心脏）和成本的限制。心室辅助装置（VAD）通过泵血与衰竭的心室并行工作，为终末期心力衰竭提供了替代治疗。上一代VAD受到并发症和耐用性问题的困扰。新一代连续流VAD（CFVAD）利用单个转子来提供血液流动，克服了旧VAD的局限性，显著减少了并发症，并实现了接近心脏移植的一年生存率;然而，仍然存在重大挑战。高达30%的CFVAD接受者经历与获得性血管性血友病因子（VWF）缺乏相关的非手术出血，认为这是由血液穿过CFVAD时经历的高剪切率引起的。一个单独的血小板粘附缺陷似乎也发生在演唱会与VWF的变化。在初步研究中，我们观察到在接受新CFVAD的VAD接受者中VWF的保存正在进行临床试验，并且在患有不同类型CFVAD的单个患者中，由于VAD植入后的自发心脏恢复，其泵速在脱机期间大幅降低。因此，获得性VWF缺乏似乎不是CFVAD固有的，并且可以随着设计或操作的改变而改变。考虑到开发CHF治疗的巨大需求和减少CFVAD显著并发症的潜力，我们建议1）使用新的微通道方法来研究CFVAD接受者中的VWF和血小板功能变化，以及2）使用改良的微通道和具有完整CFVAD的模拟循环回路，研究并量化产生观察到的VWF和血小板功能障碍的剪切条件。 公共卫生相关性：心室辅助装置有望彻底改变晚期心力衰竭的治疗。然而，包括胃和肠出血在内的并发症发生在这些设备的大约30%的接受者中。在本提案中，我们试图了解这种出血的原因以及减少或可能消除这种风险的方法。

DESCRIPTION (provided by applicant): Congestive heart failure (CHF) is a growing epidemic in the Western World, afflicting 5.5 million people in US, with an additional 550,000 new victims diagnosed each year. Even with improved medical devices, acute coronary interventions, and surgical techniques, the one and five year mortality rates for CHF are 10% and 80%, virtually unchanged in the past two decades. The only definitive therapy is heart transplantation, but that remains limited by number (2,200 donor heart available each year) and cost. Ventricular assist devices (VADs), which work in parallel with a failing ventricular by pumping blood, offer an alternative treatment for end-stage heart failure. Previous generation VADs were plagued with complications and durability concerns. A new generation of continuous flow VADs (CFVADs), which utilize a single rotor to impart blood flow are overcoming the limitations of older VADs, significantly reducing complications and achieving one year survival rates approaching that of heart transplants; however, significant challenges remain. Up to 30% of CFVAD recipients experience non-surgical bleeding related to an acquired von Willebrand Factor (VWF) deficiency, thought to be caused by the high shear rates blood experiences as it traverses through the CFVAD. A separate platelet adhesion defect also appears to occur in concert with the VWF alternations. In preliminary studies, we have observed preservation of VWF in VAD recipients with a new CFVAD undergoing clinical trials and in a single patient with a different type of CFVAD whose pump speed was substantially reduced during weaning due to spontaneous cardiac recovery post-VAD implant. Thus, the acquired VWF deficiency does not appear to be inherent to CFVADs and may be altered with changes in design or operation. Given the tremendous need to development treatments for CHF and the potential to reduce a significant complication of CFVAD, we propose to 1) Use a novel microchannel approach to investigate VWF and platelet functional alternations in CFVAD recipients and 2) Using modified microchannels and mock circulatory loops with integral CFVADs, investigate and quantify the shear conditions which produce the observed VWF and platelet dysfunction. PUBLIC HEALTH RELEVANCE: Ventricular assist devices offer the promise to revolutionize the treatment of advanced heart failure. However, complications including bleeding of the stomach and intestines occurs in about 30% of recipients of these devices. In this proposal we seek to understand the causes of this bleeding and ways to reduce or possibly eliminate this risk.