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

项目摘要 连续流动心室辅助装置（CF-VAD）的主要问题是所产生的非生理性心脏病。 搏动性降低的血流已被证明是动静脉畸形发展的主要风险因素 畸形（AVM）和胃肠道（GI）出血。为了解决这个问题，通过快速的流量调节， 已经提出改变泵叶轮速度作为引入“人工脉动”的技术。然而，在这方面， 由于大型动物模型不足以重现CF-VAD相关的非手术出血事件， 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如何， 必要为了评估脉动性的影响，并确定有前途的流量调制方法，我们开发了 血管脉冲灌注模型（VPPM），在以下条件下培养人主动脉内皮细胞（HAECs） 正常脉动流或脉动性减弱的血流（CF-VAD支持）。我们建立动脉模型的基本原理 血管是因为脉动主要影响循环系统的动脉侧，其影响是 由排列在大动脉血管上的内皮细胞转导。VPPM被验证为相关模型 通过直接比较有和没有CF-VAD的患者的主动脉样本。我们公布的数据还显示， 脉动性的丧失与促血管生成/炎性细胞因子产生的增加有关。的 这些结果的相关性通过来自经历AVM的患者的支持数据得到进一步加强， 胃肠道出血事件（CF-VAD相关和其他疾病所致）显示类似的前- 血管生成/炎性细胞因子。因此，VPPM提供了一个强大的模型来评估人工 在CF-VAD流量调节的背景下，确定是否恢复脉压和/或脉搏 频率可以减轻非手术出血事件。根据最近的研究表明， < 35 mmHg是发生胃肠道出血的主要风险因素，我们假设“脉动性减弱 与“CF-VAD支持”相关的结果是内皮功能障碍和促炎/促血管生成可溶性 生产要素。这些变化可以通过使用流量调制引入人工脉动来缓解 其中脉压保持在> 35 mmHg的策略”。Aim 1将评价患者的缓解 VPPM内的内皮细胞到CF-VAD流动并定量血管生成/炎性可溶性因子 Aim 2将对患者进行长达36个月的随访，以评估促血管生成/促血管生成的血清水平。 炎性细胞因子和非手术出血事件，然后将其与体外结果进行比较 VPPM和Aim 3中的研究将使用患者源性 内皮细胞，通过比较血流动力学确定最有前途的患者特异性方法 使用深度学习方法的细胞因子和细胞因子生物标志物。该项目的成功完成将 能够识别基于器械的策略，以预防接受CF-VAD支持的患者的非手术出血。

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.