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: 10116660
• 负责人: Palaniappan Sethu
• 金额: $ 59.37万
• 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/10116660
• 关键词: Activities of Daily Living; Address; Adverse event; Affect; Age-Years; Aging; Animal Model; Animals; Antioxidants; Arteriovenous malformation; Biological Markers; Blood Vessels; Blood specimen; Brain hemorrhage; Cardiovascular system; Cell Line; 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; 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; base; cytokine; deep learning; endothelial dysfunction; experience; gastrointestinal; 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.

项目概要 连续流心室辅助装置 (CF-VAD) 的一个主要问题是由此产生的非生理效应 脉动减弱的血流已被证明是动静脉发育的主要危险因素 畸形（AVM）和胃肠道（GI）出血。为了解决这个问题，通过快速流量调节 有人提出改变泵叶轮速度作为引入“人工脉动”的技术。然而， 鉴于大型动物模型不足以重建 CF-VAD 相关的非手术出血事件， 目前尚不清楚人工搏动是否可以预防这些不良事件，或者人工搏动的水平是多少 必要的。为了评估脉动的影响并确定我们开发的有前途的流量调节方法 在一定条件下培养人主动脉内皮细胞 (HAEC) 的血管脉冲灌注模型 (VPPM) 正常脉动血流或脉动减弱的血流（CF-VAD 支持）。我们对动脉建模的基本原理 血管是因为搏动主要影响循环系统的动脉侧，其影响是 由大动脉血管内皮细胞转导。 VPPM 被验证为相关模型 通过直接比较患有和不患有 CF-VAD 的患者的主动脉样本。我们公布的数据还显示 搏动性的丧失与促血管生成/炎症细胞因子的产生增加有关。这 通过支持经历 AVM 的患者的数据，这些结果的相关性得到进一步加强 胃肠道出血事件（CF-VAD 相关的和其他情况引起的）显示出类似的促- 血管生成/炎症细胞因子。因此，VPPM 提供了一个强大的模型来评估人工 CF-VAD 流量调制背景下的脉动性并确定是否恢复脉压和/或脉搏 频率可以减少非手术出血事件。根据最近的研究表明脉压 < 35 mmHg 是发生胃肠道出血的主要危险因素，我们假设“搏动减弱 与“CF-VAD 支持”相关导致内皮功能障碍和促炎/促血管生成可溶性 要素生产。这些变化可以通过使用流量调制引入人工脉动来减轻 将脉压保持在 > 35 mmHg 的策略”。Aim1 将评估患者的反应 VPPM 内的内皮细胞向 CF-VAD 流动并量化血管生成/炎症可溶性因子 Aim2 将跟踪患者长达 36 个月，以评估促血管生成/促血管生成的血清水平 炎症细胞因子和非手术出血事件，然后与体外结果进行比较 VPPM 和 Aim3 内的研究将使用患者来源的数据来评估不同的流量调节策略 内皮细胞通过比较血流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。该项目的顺利完成将 能够确定基于设备的策略，以防止接受 CF-VAD 支持的患者发生非手术出血。