Effective diagnosis of COA hinges on quantifications of the global hemodynamics (heart function metrics and workload), and the local hemodynamics (3-dimensional flow dynamics in COA). In this study, we developed an image-based framework that can quantify local and global hemodynamics for COA diagnosis. The proposed framework uses lattice Boltzmann method and lumped-parameter modeling that only needs routine non-invasive clinical patient data. The computational framework was validated against clinical cardiac catheterization data and Doppler echocardiographic measurements. One of the complicating factors of COA is its common association with mixed valvular diseases (MVD), which include varying combinations of aortic and mitral valve pathologies. Treatment strategies for these patients are quite unclear and differ from patient to patient. In order to evaluate risk factors and create guidelines for intervention aimed at minimizing the progression of cardiovascular disease, the impact of COA and MVD on aortic fluid dynamics in patients with COA and MVD was investigated in this thesis. Our results show that interaction of MVD with COA fluid dynamics may amplify adverse hemodynamic effects especially downstream of COA and may contribute to speed up the progression of the disease. The results suggest that some more aggressive surgical approaches may be required as regularly chosen current surgical techniques may not be optimal for patients with both COA and MVD. The appropriate surgical technique for COA repair often remains unclear for adult patients. Extra-anatomical bypass grafting has been recommended in some of the COA cases. To effectively evaluate risk status and create guidelines for intervention, precise quantification of aortic fluid dynamics and hemodynamics is required. We used a patient-specific numerical framework to investigate the impact of bypass grafts on aortic fluid dynamics in patients with COA. This study can partially explain the complications associated in patients with COA who underwent bypass grafting. / Dissertation / Doctor of Philosophy (PhD) / Coarctation of the aorta is a congenital narrowing of the proximal descending aorta which coexists with other cardiovascular diseases. Although accurate and early diagnosis of coarctation hinges on blood flow quantification, proper diagnostic methods for coarctation still lack because fluid-dynamics methods that can be used for accurate flow quantification are not well developed yet. We developed an image-based patient-specific computational framework that can quantify hemodynamics in patients with coarctation. Moreover, we investigated the impact of coarctation coexisting with other diseases and its interventions on hemodynamics to answer clinical questions.

Coarctation of the aorta (CoA) is a congenital heart disease in which the aorta witnesses localized obstruction. CoA can be fatal if left untreated. Endovascular stenting of CoA is an attractive treatment of choice in adolescents and adults; however, it can be associated with problems like stent malapposition and inappropriate stent expansion. The main objective of this study is to investigate the effects of stent implantation on the hemodynamic factors in a patient with mild coarctation. Computational fluid dynamics was utilized to illustrate the hemodynamic factors like velocity distribution, wall shear stress, and trans-coarctation pressure drop in pre- and post-intervention states. These factors were used to assess the success of stent deployment in this patient. Large Eddy Simulation (LES) model is employed in this work to provide detailed information on hemodynamics in patient-specific preand post-intervention geometries of the aorta. The results of an in-house lumped parameter code, in which its input parameters are obtained from patient-specific clinical data, were applied as the boundary conditions in this study. / Thesis / Master of Applied Science (MASc)

Background: Coarctation of the aorta (CoA) is a congenital heart disease which represents a narrowing of the proximal descending aorta, hence increasing pressure afterload to the left ventricle (LV). Conventional treatment of native CoA is surgical repair, however potential recurrence or other related complications e.g. aortic rupture, heart failure and cerebrovascular events are common. Thus, lifelong follow-up of these patients is required. Echocardiography is the most patient’s friendly method to evaluate CoA and in particular its effect on LV function. Moreover, the novel speckle tracking echocardiography (STE) is an important method to assess subclinical LV dysfunction, a technique that promises better evaluation of LV function in these patients. The aims of this thesis were to review the literature on LV function in children with CoA using myocardial deformation imaging technologies, hence, to better understand the current knowledge and vagueness of the scientific evidence. We also aimed to study the effect of early CoA repair on the structure and function of LV and ascending aorta. In addition, we wished to establish in a meta-analysis format normal values of speckle tracking derived strain and strain rate values. Methods: Study 1. We have systematically searched the PubMed, and studies that fulfilled the inclusion criteria were critically analyzed and presented on a narrative form. Study 2 and 3. In addition to conventional echocardiographic measures of LV and ascending aorta, we measured longitudinal strain and strain rate of the LV using a vendor independent software, TomTec. We have also measured the aorto-septal angle (AoSA). Data was compared with normal healthy controls. Study 4. Electronic databases were systematically searched and suitable studies were meta analyzed using Comprehensive meta-analysis version 3 software. Results: Study 1. In 7/4945 included articles, 123 and 76 patients with congenital aortic stenosis (CAS) and CoA were reported, respectively. Normal conventional LV function, with subclinical myocardial dysfunction were reported in all studies before intervention. After intervention, a consistent improvement of myocardial deformation parameters was documented, even though not reaching normal values. Study 2. In 21 patients with CoA, LV function significantly improved after intervention (p <0.001), however normal values were not reached even at medium-term follow-up (p = 0.002). Medium-term longitudinal strain correlated with pre intervention LV ejection faction (EF) (r = 0.58, p = 0.006). Medium-term subnormal values were more frequently associated with Bicuspid aortic valve (BAV) (33.3% vs. 66.6%; p <0.05). Study 3. AoSA was abnormally wide before intervention, in particular at peak ejection in the descending aorta (p <0.0001), and correlated with CoA pressure gradient. After intervention, AoSA normalized and significantly correlated with the increase of LV cavity function and overall LV deformation parameters. Study 4. In a meta-analysis of 28/282 studies including 1192 subjects, strain and strain rate values were established. Longitudinal strain normal mean values varied from -12.9 to -26.5 (mean, -20.5; 95 % CI, -20.0 to -21.0). Normal mean values of circumferential strain varied from -10.5 to -27.0 (mean, -22.06; 95 % CI, -21.5 to -22.5). Radial strain normal mean values varied from 24.9 to 62.1 (mean, 45.4; 95 % CI, 43.0 to 47.8). Meta-regression showed LV end-diastolic diameter as a significant determinant of variation of longitudinal strain. Longitudinal systolic strain rate was significantly determined by age and radial strain was influenced by the type of vendor used. Conclusion: The systematic review showed subclinical LV dysfunction in children with CoA before and after correction. However, since most of the patients were operated at an older age and had preserved LV EF, the effect of early intervention on LV function was only speculated. Our children with CoA who were operated at an earlier age showed LV subclinical dysfunction even at medium- term after intervention while the AoSA returned to normal shortly after intervention. Lower longitudinal strain values were found in patients with LV dysfunction (LV EF <50%) before intervention and BAV. Finally, normal range values for strain and strain rate have been established and seem to be influenced by patients’ age, LV end-diastolic diameter and vendor used.

Background Coarctation of the aorta (CoA) constitutes 5-8 % of all congenital heart disease (CHD) and is associated with long-term complications such as hypertension (HTN) and left ventricular hypertrophy (LVH). Factors associated with HTN, LVH, and diffuse myocardial fibrosis, are not yet fully explored in this population. Methods Papers I-III: The Swedish national register of congenital heart disease (SWEDCON) was used to identify adult patients with repaired CoA. Paper IV: Data on 2,424 adult patients with CHD was extracted from SWEDCON and compared to controls (n = 4,605) regarding height, weight and body mass index (BMI). Paper V: Adults with CoA (n = 21, age 28.5 (19.1-65.1) years, 33.3 % female) referred for CMR were investigated with T1 mapping to determine left ventricular extracellular volume fraction (ECV). Results Papers I-II: Out of 653 patients, 344 (52.7 %) had HTN. In a multivariable model, age (years) (OR 1.07, CI 1.05-1.10), sex (male) (OR 3.35, CI 1.98-5.68) and BMI (kg/m2) (OR 1.09, CI 1.03-1.16) were associated with having HTN, and so was systolic arm-leg blood pressure (BP) gradient where an association was found at the ranges (10, 20] mmHg (OR 3.58, CI 1.70-7.55) and > 20 mmHg (OR 11.38, CI 4.03-32.11), in comparison to the range [0, 10] mmHg. When investigating 243 patients with diagnosed HTN, 127 (52.3 %) had elevated BP (≥ 140/90 mmHg). Age (years) (OR 1.03, CI 1.01-1.06) was associated with elevated BP, and so was systolic arm-leg BP gradient in the ranges (10, 20] mmHg (OR 4.92, CI 1.76-13.79), and > 20 mmHg (OR 9.93, CI 2.99-33.02), in comparison to the reference interval [0, 10] mmHg. Patients with elevated BP had more classes of anti-hypertensive medication classes prescribed (1.9 vs 1.5, p = 0.003). Paper III: Out of 506 patients, 114 (22.5 %) were found to have LVH. Systolic BP (mmHg) (OR 1.02, CI 1.01-1.04), aortic valve disease, (OR 2.17, CI 1.33–3.53), age (years) (OR 1.03, CI 1.01–1.05), and HTN (OR 3.02, CI 1.81-5.02), were associated with LVH, while sex (female) (OR 0.41, CI 0.24-0.72) was negatively associated with LVH. Paper IV: There was no difference in height, weight, or BMI between patients with CoA (n = 414) and the reference population. Paper V: In the population of 21 patients, an increased left ventricular myocardial ECV was found in 6 cases (28.6 %). Of the patients with increased ECV, 5/6 (83.3 %) were female (p = 0.002). Patients with increased ECV did not otherwise differ from the rest of the study population. iv Conclusions In adults with repaired CoA, HTN and LVH were common, and many patients with HTN had elevated BP despite treatment. The potentially modifiable factors BMI and systolic arm-leg BP gradient were associated with HTN, and the gradient was also associated with elevated BP among patients with diagnosed HTN. The gradient’s significance remained even within what the current guidelines consider acceptable ranges. Potentially modifiable factors associated with LVH were systolic BP and aortic valve disease. We found no general difference in height, weight, or BMI between patients with CoA and the reference population. While LVH was more common among men, increased myocardial ECV was more common among women.