Shear-Induced Hemostatic Dysfunction and Bleeding in CF-VAD Patients

 描述(由申请人提供)：心力衰竭(HF)在美国影响510万成年患者。大约50%被诊断患有心力衰竭的人将在5年内死亡。心室辅助装置(VAD)治疗已经发展成为晚期心力衰竭患者的标准治疗方法，不仅是通往心肌恢复或心脏移植的桥梁，而且也是一种目的治疗。最近的数据表明，大约85%和75%的患者接受持续血流VADs(CF-VADs)支持将分别在12个月和24个月存活。这些存活率接近心脏移植患者的存活率。然而，出血已经成为CF-VAD治疗的一个重要问题。因此，了解CF-VAD支架的出血风险及其潜在的机制来源是至关重要的。鉴于CF-VAD治疗终末期心力衰竭患者的潜力，以及减少与设备相关的重大并发症的需要，我们建议进行一系列临床、生物和生物工程实验，以寻求更好地了解使用CF-VAD的心力衰竭患者的剪切性止血功能障碍(SIHD)和出血，以及它们与CF-VAD的血流动力学和心力衰竭患者既往存在的止血障碍的联系。此外，我们试图揭示SIHD的潜在分子机制，以更好地进行医疗管理，并创建SIHD的数据库，用于VAD设计的改进。拟议项目的三个具体目标是：(1)确定CF-VAD支持前和支持期间心衰患者SIHD的生物标记物的时间变化，并将这些变化与植入后出血事件联系起来；(2)建立CF-VAD的剪应力指数(SSI)模型，并将它们与测量的CF-VAD患者的SIHD和出血的生物标记物联系起来，同时考虑到在接受CF-VAD之前已存在的止血障碍和患者特有的SIHD对SSI的敏感性；以及(3)阐明与CF-VAD相关的SIHD的潜在分子机制，并建立用于VAD设计改进的SIHD生物标志物数据库。总之，临床血液学、生物学和生物工程方法的结合将被用来获得出血并发症背后的基本知识，并调查特定设备特定的非生理液体的影响。 SIHD的动态特性，如剪应力和曝光时间。该项目的成功完成将创造与CF-VAD相关的出血的新知识。临床医生可以利用这一新知识来改进患者的出血风险分层，以提高生活质量，工程师也可以利用这一新知识来开发创伤更小、下一代生物兼容的VAD。

 DESCRIPTION (provided by applicant): Heart failure (HF) affects 5.1 million adult patients in the US. About 50% of people diagnosed with HF will die within 5 years. Ventricular assist device (VAD) therapy has evolved into a standard therapy for patients with advanced HF, not only as a bridge to myocardial recovery or cardiac transplantation but also as a destination therapy. The recent data suggest that approximately 85 and 75% of patients supported with continuous flow VADs (CF-VADs) will survive at 12 and 24 months, respectively. These survival rates are approaching those of heart transplant patients. However, bleeding has become a significant problem for the CF-VAD therapy. Thus it is critical to understand the bleeding risk of CF-VAD support and their underlying mechanistic origins. Given the potential of the CF-VAD therapy for end-stage HF patients and the need to reduce significant device associated complications, we propose to conduct a series of clinical, biological and bioengineering experiments to seek a better understanding of shear-induced hemostatic dysfunction (SIHD) and bleeding in HF patients supported with CF-VADs and their link to blood flow dynamics of CF-VADs and pre-existing hemostatic disorder of HF patients. Further we seek to uncover the underlying molecular mechanisms of SIHD for better medical management and to create a database of SIHD for VAD design refinements. Three specific aims of the proposed project are: (1) To determine temporal changes of biomarkers of SIHD in HF patients prior to and during CF-VAD support and to link these changes to post-implant bleeding events; (2) To model shear stress indices (SSI) of CF-VADs and link them to measured biomarkers of SIHD and Bleeding in CF- VAD patients with consideration of pre-existing hemostatic disorder and patient-specific SIHD sensitivity to SSI prior to receiving a CF-VAD; and (3) To elucidate underlying molecular mechanisms of SIHD associated with CF-VADs and to establish a database of biomarkers of SIHD for VAD design improvement. Altogether, a combination of clinical hematology, biological as well as bioengineering approaches will be used to derive the basic knowledge behind bleeding complications and to investigate the influence of device-specific non- physiological fluid dynamic characteristics like shear stress and exposure time on SIHD. The successful completion of this project will create a new knowledge of bleeding associated with CF-VADs. The new knowledge can be used by clinicians to refine bleeding risk stratification in patients for the improved quality of life and by engineers to develop less traumatic, next generation biocompatible VADs.