SUMMARY Single ventricle (SV) malformations are among the most complex congenital heart defects (CHDs), affecting about 2 per 1000 births in the United States. Common palliation for SV patients is the staged Fontan procedure. This procedure culminates in a total cavopulmonary connection (TCPC), designed to connect systemic and pulmonary circulations in series. Immediate post-procedural outcomes are usually favorable. However, various long-term complications afflict the Fontan population, and many are associated with Fontan obstruction. Previous studies define Fontan obstruction as vessel narrowing or elevated energetics in the TCPC; however, they often overlook the performance of the patient’s ventricle, the core issue of SV malformations. Consequently, only weak correlations were observed between formerly defined Fontan obstruction and long-term complications in Fontan patients. Therefore, this proposed work will focus on two prevalent Fontan complications, diminished quality of life (QoL) and reduced exercise performance, to (1) identify an innovative definition of Fontan obstruction that integrates TCPC geometry and/or TCPC hemodynamics with ventricular performance and (2) to quantify the level of newly defined Fontan obstruction for optimal QoL and exercise performance in Fontan patients. Two specific aims will accomplish this project: (1) Quantify Fontan obstruction as a marker of quality of life. The working hypothesis is that an obstruction metric that integrates TCPC geometry and/or TCPC hemodynamics with ventricular performance at rest will provide a better quantification of Fontan obstruction and serve as a marker of QoL. (2) Quantify Fontan obstruction as a marker of exercise performance. This aim hypothesizes that an obstruction metric that integrates TCPC geometry and/or TCPC hemodynamics with ventricular performance (under resting conditions, exercise conditions, and/or the rest-exercise difference) will provide a better quantification of Fontan obstruction and serve as a marker of exercise capacity. Both aims will use cutting-edge, validated computational fluid dynamics and fluid-structure interaction modeling to obtain TCPC hemodynamics and ventricular performance, respectively. The proposed work is of great impact due to its goals of better quantifying Fontan obstruction to improve QoL and exercise performance for Fontan patients. Furthermore, this proposal will enhance undergraduate research and education for the recently established biomedical engineering department at the University of Massachusetts at Lowell. Undergraduate involvement in this project will allow students to experience a broad spectrum of state-of-the-art techniques and acquire skills such as medical image processing and image-based cardiovascular simulations. Additionally, the students will develop a vast network of partnerships among scientists and clinicians from national and international institutions. 1