Impact of Blood Viscosity and Vascular Compliance on Fontan Circulation Dysfunction in Children

项目概要/摘要 Fontan手术大大提高了单心室先天性心脏病患儿的存活率 缺陷不幸的是，大多数人会发展为多器官功能障碍，所有人都面临着逐渐增加的风险， Fontan失败和过早死亡。由于对病理生理学的不完全理解，Fontan失败 仍然很难预测和治疗。虽然手术会产生同样的根本性异常循环， 通过将低剪切全身静脉血从心脏重定向到肺， Fontan失败的时间和表现的可变性无法解释。计算流体力学（CFD） 已经使用建模来证明跨Fontan管道和肺脉管系统的功率损耗 是循环性能的重要但不完全的决定因素。虽然功率损失是由于粘性 由于血液中剪切力的能量损失，先前的研究忽略了血液的几个重要特征， 粘度，最显著的是其在低剪切速率下呈指数增加的性质（“非牛顿行为”）。 [NNB]），如Fontan循环。本项目的目标是：（一）阐明 NNB影响体内Fontan循环性能;以及（ii）将性能指标与临床标志物相关联 Fontan失败基于已发表的和初步的体外观察，中心假设是患者- 由血管顺应性和心输出量调节的血液NNB的特定变化决定Fontan 循环性能和临床结果。这项建议的理由是， 非牛顿粘度在Fontan循环病理生理学将作为一个框架， 筛选Fontan失败的敏感工具和预防Fontan失败的药物治疗。这项建议 将利用来自洛杉矶儿童医院、洛杉矶大学 南加州、加州-欧文大学和威斯康星州大学。使用CFD的组合 建模，4D流动磁共振成像，血液粘度分析和运动测试，以研究 种族多样的儿童Fontan患者横断面队列，中心假设将通过 追求这些具体目标：（1）确定NNB中患者特异性差异在多大程度上解释了 Fontan循环性能的变异性;（2）确定区域血管顺应性 调节NNB;（3）确定非牛顿功率损失对运动能力的预测值。的 K23机制将允许PI完成一个强大的职业发展计划，包括正式的课程， 研究设计，统计和工程，并在CFD建模和4D流动MRI的实践培训。在一起， 研究计划和职业发展活动将支持PI的长期目标， 独立资助的医生科学家，专注于研究先天性心脏病儿童的血管生物力学 心脏病，以提高心脏代偿失调的诊断和管理。

PROJECT SUMMARY/ABSTRACT The Fontan surgical procedure has greatly improved survival in children born with univentricular congenital heart defects. Unfortunately, most will develop multiorgan dysfunction, and all face a progressively increasing risk of Fontan failure and premature death. Due to an incomplete understanding of the pathophysiology, Fontan failure remains difficult to predict and treat. While the surgery creates the same fundamentally abnormal circulation and vascular dysfunction in all patients by redirecting low-shear systemic venous blood from the heart to the lungs, the variability in timing and presentation of Fontan failure is unexplained. Computational fluid dynamic (CFD) modeling has been used to demonstrate that power loss across the Fontan conduit and pulmonary vasculature is a significant but incomplete determinant of circulation performance. Although power loss is due to viscous energy loss from shear forces in blood, prior studies have overlooked several important features of blood viscosity, most notably its property of increasing exponentially at low shear rates (“non-Newtonian behavior” [NNB]), such as in the Fontan circulation. The objectives of this project are to (i) elucidate the extent to which NNB affects Fontan circulation performance in vivo; and (ii) correlate performance metrics with clinical markers of Fontan failure. Based on published and preliminary in vitro observations, the central hypothesis is that patient- specific variation in the NNB of blood, modulated by vascular compliance and cardiac output, determines Fontan circulatory performance and clinical outcomes. The rationale for this proposal is that characterization of the role of non-Newtonian viscosity in Fontan circulation pathophysiology will serve as a framework for developing sensitive tools to screen for Fontan failure and pharmacologic therapies to prevent Fontan failure. This proposal will harness the strengths of a multidisciplinary team from Children’s Hospital Los Angeles, University of Southern California, University of California - Irvine, and University of Wisconsin. Using a combination of CFD modeling, 4D flow magnetic resonance imaging, blood viscosity analysis, and exercise testing to study an ethnically diverse cross-sectional cohort of pediatric Fontan patients, the central hypothesis will be tested by pursuing these specific aims: (1) Determine the extent to which patient-specific differences in NNB explain variability in Fontan circulation performance; (2) Determine the extent to which regional vascular compliance modulates NNB; and (3) Determine the predictive value of non-Newtonian power loss on exercise capacity. The K23 mechanism will allow the PI to complete a robust career development plan including formalized curricula in study design, statistics, and engineering, and hands-on training in CFD modeling and 4D flow MRI. Together, the research plan and career development activities will support the PI’s long-term goal of becoming an independently funded physician-scientist, focusing on studying vascular biomechanics in children with congenital heart disease in order to improve the diagnosis and management of cardiac decompensation.