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

血液粘度和血管顺应性对儿童Fontan循环障碍的影响

• 批准号: 10350382
• 负责人: Andrew L Cheng
• 金额: $ 16.98万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350382
• 关键词: 4D MRI; Accounting; Affect; Behavior; Biomechanics; Blood; Blood Circulation; Blood Vessels; Blood Viscosity; Blood flow; California; Cardiac; Cardiac Catheterization Procedures; Cardiac Output; Cardiopulmonary; Caring; Cessation of life; Child; Childhood; Chronically Ill; Clinical; Clinical Markers; Complex; Computer Models; Congenital Heart Defects; Cyanosis; Data; Development; Development Plans; Diagnosis; Educational Curriculum; Electrical Engineering; Engineering; Exercise; Exercise Test; Face; Failure; Functional disorder; Funding; Geometry; Goals; Heart; Heart Diseases; Heart Transplantation; In Vitro; Interdisciplinary Study; Liquid substance; Liver Failure; Los Angeles; Lung; Lymphatic; Magnetic Resonance Imaging; Mentored Patient-Oriented Research Career Development Award; Mission; Modeling; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Organ; Outcome; Patients; Pediatric Hospitals; Pediatric cardiology; Pediatric cohort; Performance; Persons; Pharmacology; Physicians; Physiologic pulse; Population; Predictive Value; Prevention; Prognostic Marker; Property; Public Health; Publishing; Pulmonary artery structure; Research; Research Design; Research Personnel; Research Project Grants; Rest; Risk; Role; Scientist; Single ventricle congenital heart disease; Testing; Therapeutic Intervention; Training; Translating; Universities; Variant; Vascular Diseases; Venous; Ventricular Dysfunction; Viscosity; Wisconsin; aged; base; cardiac magnetic resonance imaging; career development; cohort; congenital heart disorder; ethnic diversity; exercise capacity; experience; improved; in vivo; mortality; multidisciplinary; novel; premature; prevent; shear stress; statistics; tool

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.

项目概要/摘要 Fontan 手术极大地提高了单心室先天性心脏病儿童的生存率 缺陷。不幸的是，大多数人都会出现多器官功能障碍，并且所有人都面临着逐渐增加的风险 Fontan 衰竭和过早死亡。由于对病理生理学的不完全了解，Fontan 失败 仍然难以预测和治疗。虽然手术造成了同样的根本性异常循环和 通过将低剪切全身静脉血从心脏重新引导至肺部来治疗所有患者的血管功能障碍， Fontan 衰竭的时间和表现的变化无法解释。计算流体动力学 (CFD) 模型已用于证明 Fontan 导管和肺脉管系统的功率损失 是循环性能的重要但不完整的决定因素。虽然功率损失是由于粘性造成的 由于血液中剪切力造成的能量损失，先前的研究忽略了血液的几个重要特征 粘度，最显着的是其在低剪切速率下呈指数增加的特性（“非牛顿行为” [NNB]），例如在 Fontan 循环中。该项目的目标是 (i) 阐明在多大程度上 NNB影响体内Fontan循环性能； (ii) 将表现指标与临床标志物相关联 Fontan 失败。根据已发表的和初步的体外观察，中心假设是患者 血液 NNB 的特定变化由血管顺应性和心输出量调节，决定了 Fontan 循环性能和临床结果。该提案的基本原理是角色的特征 Fontan 循环病理生理学中非牛顿粘度的研究将作为开发框架 筛选 Fontan 失败的敏感工具和预防 Fontan 失败的药物疗法。这个提议 将利用洛杉矶大学儿童医院多学科团队的优势 南加州大学、加州大学欧文分校和威斯康星大学。结合使用 CFD 建模、4D 血流磁共振成像、血液粘度分析和运动测试来研究 种族多样化的儿童 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 中患者特异性差异的解释程度 Fontan 循环性能的可变性； (2)确定局部血管顺应性的程度 调节 NNB； (3)确定非牛顿功率损失对运动能力的预测价值。这 K23机制将允许PI完成稳健的职业发展计划，包括正式课程 研究设计、统计学和工程，以及 CFD 建模和 4D 流 MRI 方面的实践培训。一起， 研究计划和职业发展活动将支持 PI 成为一名 独立资助的医师科学家，专注于研究先天性儿童血管生物力学 心脏病，以改善心脏失代偿的诊断和治疗。