Few therapeutic alternatives exist for patients with a failing single ventricle physiology. To address this need, this thesis project investigated two new therapeutic alternatives, which sought to positively augment the Fontan hemodynamics. The first modality introduced a non-invasive method of external pressure application to the lower extremities. A clinical study (n=2) was conducted, and results indicated an increase in flow as a consequence to an increase in transmural pressure in the lower extremities. The second modality investigated a minimally invasive blood pump. Numerical analyses of the pump were performed to examine hydraulic performance under physiologic conditions. The pump produced pressure rises of 1 to 25 mmHg over flows of 1 to 4 LPM, has a blood damage index less than 1% and was also found to successfully augment the hydraulic energy of the Fontan physiology. This work resulted in substantial progress to develop both modalities and address a significant human health problem.

Congenital heart disease (CHD) is the most common congenital anomaly, with single ventricle (SV) defects accounting for nearly 10% of all CHD. SV defects tend to be the most severe forms of CHD: all patients born with SV require multiple open heart surgeries, often beginning in the neonatal period, ultimately leading to the Fontan procedure. Due to improvements in surgical procedures and medical care, more patients are surviving into adolescence and adulthood. Brain imaging and pathology studies have shown that patients with SV have differences in brain structure and metabolism even before the first surgery, and as early as in utero. Furthermore, a significant number of patients have new or more severe lesions after the initial surgery, and many still have brain abnormalities into early childhood. However, there are no detailed brain structural data of SV patients in adolescence. Our group recruited a large cohort of post-Fontan SV patients aged 10-19 years. Separate analyses of neuropsychological and behavioral outcomes in these patients show deficits in multiple areas of cognition, increased rates of attention deficit-hyperactivity disorder (ADHD), and increased use of remedial and/or special education services compared to a control group. Post-Fontan adolescents have more gross brain abnormalities, including evidence of chronic ischemic stroke. Furthermore, there are widespread reductions in cortical and subcortical gray matter volume and cortical thickness, some of which are associated with medical and surgical variables. Diffusion tensor imaging (DTI) analyses show widespread areas of altered white matter microstructure in deep subcortical and cerebellar white matter. In this dissertation, I use graph theory methods to characterize structural connectivity based on gray matter (cortical thickness covariance) and white matter (DTI tractography), and examine associations between brain structure and neurodevelopment. I found that brain network connectivity differs in post-Fontan patients compared with controls, both at the global and regional level. Additionally, deficits in overall network structure were associated with impaired neurodevelopment in several domains, including general intelligence, executive function, and visuospatial skills. These data suggest that early neuroprotection should be a major focus in the care of SV patients, with the goal of improving long-term neurodevelopmental outcomes.

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BACKGROUND: Hypoplastic Left Heart Syndrome is a congenital birth defect that is defined by underdevelopment of the left heart during pregnancy. This is especially dangerous as the left heart holds the systemic flow of blood- the oxygenated blood. Not enough oxygen throughout the whole body causes cyanosis, which symptoms include bluish discoloration of the skin or mucous membrane due to low oxygen saturation. Single Ventricle Palliation followed by Biventricular Conversion is the most common surgical procedural pathway to correct this defect. The goal is to convert from a single ventricle circulation during single ventricle palliation to biventricular circulation via biventricular conversion, which is the normal heart anatomy. Single Ventricle Pallation consists of three stages: Stage 1 Norwood Procedure, Bidirectional Glenn, and Fontan. Biventricular Conversion can be performed after any of the three stages. In addition, further compromise of the left ventricle includes other factors such as a thickening of fibroblast-like cells on the endocardial layer called endocardial fibroelastosis. Therefore, additional surgical procedures, also known as recruitment procedures, combat these problems. It is critical to find a correlation between a specific procedure and post surgery success in left ventricle growth and function for these patients. OBJECTIVES: Patients with Hypoplastic Left Heart Syndrome at Boston Children’s Hospital have undergone single ventricle palliation with some patients proceeding to biventricular conversion. This study aimed to study the palliation stages individually and recruitment procedures (specifically endocardial fibroelastosis resection) on the effect of left ventricle growth. METHODS: Patients with Hypoplastic Left Heart Syndrome were studied retrospectively (before 2014) and prospectively (after 2014 until December 1, 2018). Single Ventricle Palliation and Biventricular Conversion were analyzed via descriptional analysis with evidence of left ventricular growth measured by left ventricular end diastolic volume and respective z-scores. Z-scores were used to standardize end diastolic volume values across variability in age, weight, and height. RESULTS: A total of 55 patients underwent single ventricle palliation and 39 ended with biventricular circulation via biventricular conversion. Overall, there was a 9.29 ml increase in end diastolic volume between Bidirectional Glenn and Fontan and a 0.795 increase in end diastolic volume z-score between Fontan and Biventricular Conversion. Next, those who did not have recruitment procedures experienced a 135.6%, 48.8%, and 0% growth at Stage 1, Bidirectional Glenn, and Fontan, respectively, before directly proceeding to biventricular conversion. Those with recruitment experienced a 44.5%, 90.4%, and 83.0% growth at Stage 1, Bidirectional Glenn, and Fontan, respectively, before directly proceeding to biventricular conversion. Finally, there was a 50.2% and 62.3% in left ventricular growth at Bidirectional Glenn and Fontan, respectively, after endocardial fibroelastosis resection compared to only a 6.9% growth at Stage 1. CONCLUSION: Bidirectional Glenn was the most effective palliation stage for left ventricular growth. Recruitment in patients at this stage was associated with growth that exceeds those who did not have recruitment. This stage also best demonstrates the ability and success of growing a small ventricle to be adequate for biventricular conversion. Left ventricular growth at Fontan circulation holds promising results that are a point of interest for more studies. Endocardial Fibroelastosis resection is more effective on left ventricular growth at Bidirectional Glenn and Fontan compared to Stage 1.

In order to address the long-term complications that arise from poor venous return, a hallmark of the Fontan physiology, we assessed the feasibility of a non-invasive, home therapy that will improve the health of the patient during the heart transplant waiting period and ameliorate the quality of life. In order to achieve this goal we tested a device that applies pressure to the lower extremities of the body (legs and abdomen) in a pulsating fashion with the goal of augmenting systemic blood flow to the pulmonary arteries. This treatment will enhance flow from the great veins and through the lungs and serve as adjunctive clinical treatment of single ventricle physiology. The specific aim of this study was to show improvements in cardiorespiratory measurements after applying external pressure as a proxy for improved health in the Fontan patient. Various studies have shown the impaired exercise capacity of post-operative Fontan patients, but very little data exists focusing on a period much later after the surgery. Our results among the two subjects completed so far have shown a moderately beneficial improvement in exercise capacity after the compression therapy. Subjects performed a treadmill exercise stress test at VCU that was followed by six days of applied external pressure treatment and finished with a final post-treatment stress test. Cardiorespiratory data was collected and analyzed for improvements from base level. Overall an improvement in exercise duration time, VO2 peak, ventilatory threshold, and OUES was observed, with only VE / VCO2 slope having mixed results. Both subjects seem to be relatively healthy Fontan patients, as indicated by their VO2 peak, VE/VCO2 slope and OUES. As a result, benefits of treatment may vary among a cohort of Fontan patients with poor health condition; a failing Fontan physiology for instance. The improvement in exercise capacity suggests that this therapy could be very beneficial to Fontan patients. These results warrants follow up studies to explore the extent of the clinical benefits of compression treatment among the Fontan population.

Single ventricle heart defects, where systemic and pulmonary venous returns mix in the single functional ventricle, represent the most complex form of congenital heart defect, affecting 2 babies per 1000 live births. Surgical repairs, termed "Fontan Repairs," reroute the systemic venous return directly to the pulmonary arteries, thus preventing venous return mixing and restoring normal oxygenation saturation levels. Unfortunately, these repairs are only palliative and Fontan patients are subjected to a multitude of chronic complications. It has long been suspected that hemodynamics play a role in determining patient outcome. However, the number of anatomical and functional variables that come into play and the inability to conduct large scale clinical evaluations, due to too small a patient population, has hindered decisive progress and there is still not a good understanding of the optimal care strategies on a patient-by-patient basis. Over the past decades, image-guided computational fluid dynamics (CFD) has arisen as an attractive option to accurately model such complex biomedical phenomena, providing a high degree of freedom regarding the geometry and flow conditions to be simulated, and carrying the potential to be automated for large sample size studies. Despite these theoretical advantages, few CFD studies have been able to account for the complexity of patient-specific anatomies and in vivo pulsatile flows. In this thesis, we develop an unstructured Cartesian immersed-boundary flow solver allowing for high resolution, time-accurate simulations in arbitrarily complex geometries, at low computational costs. Combining the proposed and validated CFD solver with an interactive virtual-surgery environment, we present an image-based surgical planning framework that: a) allows for in depth analysis of the pre-operative in vivo hemodynamics; b) enables surgeons to determine the optimum surgical scenario prior to the operation. This framework is first applied to retrospectively investigate the in vivo pulsatile hemodynamics of different Fontan repair techniques, and quantitatively compare their efficiency. We then report the prospective surgical planning investigations conducted for six failing Fontan patients with an interrupted inferior vena cava and azygous continuation. In addition to a direct benefit to the patients under consideration, the knowledge derived from these surgical planning studies will also have a larger impact for the clinical management of Fontan patients as they shed light onto the impact of caval offset, vessel flaring and other design parameters upon the Fontan hemodynamics depending on the underlying patient anatomy. These results provide useful surgical guidelines for each anatomical template, which could benefit the global surgical community, including centers that do not have access to patient-specific surgical planning interfaces.