Selection of Flow Modulation Protocols for Patients on Continuous Flow Ventricular Assist Devices (CF-VADs)

为使用连续流心室辅助装置 (CF-VAD) 的患者选择流量调节方案

• 批准号: 10576830
• 负责人: Palaniappan Sethu
• 金额: $ 58.22万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-02 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576830
• 关键词: Activities of Daily Living; Address; Adverse event; Affect; Age Years; Aging; Animal Model; Animals; Antioxidants; Aorta; Arteriovenous malformation; Biological Markers; Blood Vessels; Blood specimen; Brain hemorrhage; Cardiovascular system; Categories; Cell Line; Cell Separation; Cells; Data; Development; Devices; Endothelial Cells; Endothelin-1; Endothelium; Event; Frequencies; Functional disorder; Gastrointestinal Hemorrhage; Heart failure; Hemorrhage; Human; In Vitro; Individual; Inflammatory; Machine Learning; Mediating; Medical; Modeling; Monitor; Operative Surgical Procedures; Organ; Patient Selection; Patients; Perfusion; Physiologic pulse; Physiological; Production; Protocols documentation; Publishing; Pulsatile Flow; Pulse Pressure; Pump; Quality of life; Quantitative Evaluations; Refractory; Regulation; Risk Factors; Sampling; Serum; Sheep; Side; Signal Transduction; Speed; Techniques; Testing; Time; Tissue Sample; Transducers; Translating; VWF gene; Validation; Work; cytokine; deep learning; endothelial dysfunction; energy efficiency; experience; hemodynamics; improved; novel strategies; operation; patient response; preservation; pressure; prevent; response; safety testing; ventricular assist device

PROJECT SUMMARY A major concern with continuous flow ventricular assist devices (CF-VADs) is the resulting non-physiological flow with diminished pulsatility which has been shown to be a major risk factor for development of arteriovenous malformations (AVMs) and gastrointestinal (GI) bleeding. To address this issue, flow modulation via rapid changes in pump impeller speed has been proposed as a technique to introduce ‘artificial pulsatility’. However, given the inadequacy of large animal models with recreating CF-VAD associated non-surgical bleeding events, it is still unclear if artificial pulsatility can prevent these adverse events or what level of artificial pulsatility is even necessary. To evaluate the effects of pulsatility and identify promising flow modulation approaches we developed a vascular pulse perfusion model (VPPM) to culture Human Aortic Endothelial Cells (HAECs) under conditions of normal pulsatile flow or flow with diminished pulsatility (CF-VAD support). Our rationale for modeling arterial vessels is because pulsatility primarily affects the arterial side of the circulatory system and its effects are transduced by endothelial cells that line the large arterial vessels. The VPPM was validated as relevant model via direct comparison with aortic samples of patients with and without CF-VADs. Our published data also shows that loss of pulsatility is associated with an increase in production of pro-angiogenic/inflammatory cytokines. The relevance of these results is further strengthened by supporting data from patients that experience AVMs and GI bleeding events (both CF-VAD related and due to other conditions) showing similar elevated levels of pro- angiogenic/inflammatory cytokines. The VPPM therefore provides a powerful model to evaluate artificial pulsatility in the context of CF-VAD flow modulation and determine if restoring pulse pressure and/or pulse frequency can mitigate non-surgical bleeding events. Based on recent studies that suggest that pulse pressure < 35 mmHg is a major risk factor for development of GI bleeds, we hypothesize that “Diminished pulsatility associated with ‘CF-VAD support’ results in endothelial dysfunction and pro-inflammatory/pro-angiogenic soluble factor production. These changes can be mitigated via introduction of artificial pulsatility using flow modulation strategies where pulse pressure is preserved at > 35 mmHg”. Aim1 will evaluate response of patient derived endothelial cells within the VPPM to CF-VAD flow and quantify angiogenic/inflammatory soluble factor production, Aim2 will follow patients for up to 36 months to evaluate serum levels of pro-angiogenic/pro- inflammatory cytokines and non-surgical bleeding events which will then be compared to results from in-vitro studies within the VPPM and Aim3 will evaluate different flow modulation strategies using patient-derived endothelial cells to determine most promising patient-specific approaches via comparison of hemodynamic profiles and cytokine biomarkers using deep learning approaches. Successful completion of this project will enable identification of device-based strategies to prevent non-surgical bleeding in patients on CF-VAD support.

项目摘要 连续流动室辅助设备（CF-VAD）的主要问题是由此产生的非生理学 脉冲性降低的流量已被证明是开发动静脉的主要危险因素 畸形（AVM）和胃肠道（GI）出血。为了解决这个问题，通过快速调制流量调制 已经提出了泵叶轮速度的变化，以作为引入“人造脉动性”的一种技术。然而， 鉴于大型动物模型不足，重现了CF-VAD相关的非手术出血事件， 目前尚不清楚人工搏动性是否可以防止这些不良事件，甚至是什么水平的人造脉动性 必要的。为了评估脉动性的影响并确定有希望的流动调制方法，我们开发了 条件下培养人主动脉内皮细胞（HAEC）的血管脉冲灌注模型（VPPM） 正常的脉动流量或流动性降低的脉冲性（CF-VAD支持）。我们为动脉建模的理由 血管的原因是脉冲性主要影响电路系统的动脉侧，其影响是 由内皮细胞转导的大动脉视频。 VPPM被验证为相关模型 通过直接与患有和没有CF-VAD的患者的正向样品进行比较。我们发布的数据也显示 脉动丧失与促血管生成/炎症细胞因子的产生增加有关。这 通过支持经历AVM和 胃肠道出血事件（CF-VAD和其他条件相关）显示出相似的促进水平 血管生成/炎症细胞因子。因此，VPPM提供了一种评估艺术的强大模型 在CF-VAD流量调制的背景下进行脉动，并确定是否恢复脉搏压力和/或脉冲 频率可以减轻非手术性出血事件。基于最近的研究表明脉搏压力 <35 mmHg是GI出血发展的主要危险因素，我们假设“脉动减弱 与“ CF-VAD支持”相关的会导致内皮功能障碍和促炎/促血管生成可溶性 因子产生。可以通过使用流量调制引入人工搏动性来减轻这些变化 保持脉冲压力> 35 mmHg的策略。 VPPM内的内皮细胞至CF-VAD流量并量化血管生成/炎症固体因子 生产，AIM2将跟踪患者长达36个月的患者，以评估血清血管生成/促血清的水平 炎性细胞因子和非手术性出血事件，然后将其与维特罗的结果进行比较 VPPM和AIM3中的研究将使用患者来评估不同的流量调制策略 内皮细胞通过比较血液动力学来确定最有前途的患者特异性方法 使用深度学习方法的概况和细胞因子生物标志物。成功完成该项目将 能够鉴定基于设备的策略，以防止CF-VAD支持患者的非手术出血。