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
基本信息
- 批准号:10576830
- 负责人:
- 金额:$ 58.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Activities of Daily LivingAddressAdverse eventAffectAge YearsAgingAnimal ModelAnimalsAntioxidantsAortaArteriovenous malformationBiological MarkersBlood VesselsBlood specimenBrain hemorrhageCardiovascular systemCategoriesCell LineCell SeparationCellsDataDevelopmentDevicesEndothelial CellsEndothelin-1EndotheliumEventFrequenciesFunctional disorderGastrointestinal HemorrhageHeart failureHemorrhageHumanIn VitroIndividualInflammatoryMachine LearningMediatingMedicalModelingMonitorOperative Surgical ProceduresOrganPatient SelectionPatientsPerfusionPhysiologic pulsePhysiologicalProductionProtocols documentationPublishingPulsatile FlowPulse PressurePumpQuality of lifeQuantitative EvaluationsRefractoryRegulationRisk FactorsSamplingSerumSheepSideSignal TransductionSpeedTechniquesTestingTimeTissue SampleTransducersTranslatingVWF geneValidationWorkcytokinedeep learningendothelial dysfunctionenergy efficiencyexperiencehemodynamicsimprovednovel strategiesoperationpatient responsepreservationpressurepreventresponsesafety testingventricular assist device
项目摘要
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GI出血的主要危险因素,我们假设“搏动性降低
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Palaniappan Sethu其他文献
Palaniappan Sethu的其他文献
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{{ truncateString('Palaniappan Sethu', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 58.22万 - 项目类别:
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:
10362551 - 财政年份:2021
- 资助金额:
$ 58.22万 - 项目类别:
Tissue Chip Models for Cardiovascular Development and Disease
心血管发育和疾病的组织芯片模型
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10335220 - 财政年份:2020
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Tissue Chip Models for Cardiovascular Development and Disease
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- 批准号:
9907698 - 财政年份:2020
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