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

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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.