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

项目摘要/摘要 Fontan手术极大地提高了出生时患有单室先天性心脏病的儿童的存活率 缺陷。不幸的是，大多数人会发展成多器官功能障碍，所有人都面临着逐渐增加的风险 方坦失败和过早死亡。由于对病理生理学的不完全了解，Fontan衰竭 仍然很难预测和治疗。虽然手术产生了同样的从根本上异常的循环和 所有患者的血管功能障碍都是通过将低切变体静脉血液从心脏重定向到肺来实现的， Fontan失败的时间和表现的变异性无法解释。计算流体力学(CFD) 模型已经被用来证明Fontan管道和肺血管系统的功率损失 是循环绩效的一个重要但不完全的决定因素。虽然电力损失是由于粘性 由于血液中剪切力的能量损失，以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长的特性(“非牛顿行为” [nnb])，例如在丰坦环流中。本项目的目标是：(I)阐明 NNb影响体内Fontan循环性能；以及(Ii)性能指标与临床标记物的相关性 方坦失败的证据。根据已发表的和初步的体外观察，中心假设是患者- 受血管顺应性和心输出量调节的血液NNB的特殊变化决定了Fontan 循环性能和临床结果。这项提议理由是对角色的描述 Fontan循环病理生理学中的非牛顿粘度将作为发展的框架 筛选Fontan衰竭和预防Fontan衰竭的药物治疗的敏感工具。这项建议 将利用来自洛杉矶大学儿童医院的多学科团队的力量 南加州大学、加州大学欧文分校和威斯康星大学。使用CFD的组合 建模、4D血流磁共振成像、血液粘度分析和运动测试，以研究 在不同种族的儿童Fontan患者横断面队列中，中心假设将通过以下方式进行验证 追求这些具体目标：(1)确定NNB患者的具体差异在多大程度上可以解释 Fontan循环性能的可变性；(2)决定区域血管顺应性的程度 调制NNB；(3)确定非牛顿功率损失对运动能力的预测值。这个 K23机制将使PI能够完成一项强有力的职业发展计划，包括#年的正式课程 学习CFD建模和4D Flow MRI的设计、统计和工程以及动手培训。一起， 研究计划和职业发展活动将支持PI成为一名 独立资助的内科科学家，专注于研究先天性心脏病儿童的血管生物力学 以提高对心脏失代偿的诊断和处理。

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.