OBJECTIVES: The association between bicuspid aortic valves and aortic aneurysms has been well documented. In order to better understand this association, this study sought to accomplish two goals. The first was to determine if there was any correlation between specific bicuspid aortic valve phenotypes and aortic aneurysms. The second goal was to determine if the association between bicuspid aortic valve disease and aortic aneurysms has a genetic or hemodynamic cause. METHODS: For the non-genetic portion of the study, we used echocardiogram and surgical records to classify the phenotypes of the aortic valve and the aorta of 434 patients. We then evaluated the correlation between valve morphotype and aortic aneurysm phenotype. For the genetic portion, we used a genome wide association study on 452 patients to find genes that could potentially be responsible for aortic aneurysms. These were then compared with genes suspected of causing bicuspid aortic valve to determine if there is a common genetic link between the two disorders. RESULTS: We observed a significant association between bicuspid aortic valve and aortic aneurysms; however we did not find any significant association between the different bicuspid aortic valve phenotypes and aortic aneurysm phenotypes. For the genome wide association study, we identified genes that could potentially be responsible for causing aortic aneurysms; however, none of the suspected markers were considered statistically significant. Also none of the identified genes matched to the genes suspected of causing bicuspid aortic valve. CONCLUSION: While the results were not as expected, the study provided us with information to better understand the relationship between bicuspid aortic valves and aortic aneurysms. According to the results of the current study, patients with bicuspid aortic valve are more likely to develop an aortic aneurysm but specific phenotype has no effect on where the aneurysm occurs in the aorta. The increased frequency of aortic aneurysms in bicuspid valve patients is most probably due to a combination of altered hemodynamics and genetic effects. In order for this information to be useful in the clinical setting, the methods of this study should be repeated in a larger cohort to make sure the results are accurate.

Heart valve dysfunction is a relatively common condition in the population, whereas significant heart valve disease is more unusual. The cause of different types of heart valve disease depends on which valve is concerned. Rheumatic heart valve disease, has for a long time been considered to constitute a post-inflammatory condition. During the 1990s it was also shown that the so-called non-rheumatic or degenerative tricuspid aortic stenosis, comprised signs of inflammation. In this study, 118 patients (the VOCIN study group) referred to the University Hospital for preoperative investigation due to significant heart valve disease, were examined regarding signs of inflammation. Twenty-nine aortic valves from patients with significant aortic stenosis were divided into tricuspid and bicuspid aortic valves. The bicuspid aortic stenotic valves revealed signs of inflammation to a similar extent as the tricuspid valves. However, the tricuspid and bicuspid valves differed regarding distribution of calcification. In contrast, inflammation was not a predominant feature in 15 aortic and mitral valves from patients with significant heart valve regurgitation. Gross valvular pathology consistent with rheumatic aortic stenosis was found in 10 patients. These valves revealed a somewhat lower degree of inflammatory cell infiltration, but on the whole, there were no substantial differences when compared to non-rheumatic aortic stenotic valves. They did, however, reveal a similar distribution of calcification as the bicuspid, non-rheumatic aortic valves. The VOCIN study group was compared to an age- and gender matched control group with regard to history and signs of rheumatic disease. There was not any increased prevalence of clinical manifestations of non-cardiac inflammatory disease in patients with significant heart valve disease, when compared to healthy control subjects. However, patients with heart valve disease had significantly increased serum levels of inflammatory markers compared to controls. The increase in inflammatory markers remained significant even in the subgroup of non-rheumatic aortic stenosis devoid of coronary artery disease. These results indicate that a systemic inflammatory component is associated with stenotic, non-rheumatic heart valve disease. The similarities between different forms of calcific aortic valve disease indicate a similar pathogenesis. The question is raised whether aortic stenosis is one disease, mainly caused by a general and non-specific response to dynamic tissue stress due to an underlying malformation of the valve.

No description available.

Congenital heart disease (CHD) is the most common birth defect in infants. Identifying factors that are critical to embryonic heart development or CHDs in general could further our understanding of the disease and may lead to new strategies of its prevention and treatment. Endothelial nitric oxide synthase (NOS3/eNOS) is known for many important biological functions including vasodilation, vascular homeostasis and angiogenesis. Previous studies have shown that deficiency in NOS3 results in congenital septal defects, cardiac hypertrophy and postnatal heart failure. In addition, NOS3 is pivotal to morphogenesis of aortic valve and myocardial capillary development. The aim of my thesis was to investigate the role of NOS3 in the embryonic and adult heart. I discovered that NOS3 deficiency resulted in coronary artery hypoplasia in fetal mice and spontaneous myocardial infarction in postnatal hearts. Coronary artery diameters, vessel density and volume were significantly decreased in NOS3-/- mice at postnatal day 0. Lack of NOS3 also down-regulated the expression of Gata4, Wilms tumor-1, vascular endothelial growth factor, basic fibroblast growth factor and erythropoietin in the embryonic heart at E12.5, and inhibited migration of epicardial cells into the myocardium. In addition, my data show that the overall size and length of mitral and tricuspid valves were decreased in NOS3-/- compared with WT mice. Echocardiographic assessment showed significant regurgitation of mitral and tricuspid valves during systole in NOS3-/- mice. Immunostaining of Snail1 was performed in the embryonic heart. Snail1 positive and total mesenchymal cells in the AV cushion were decreased in NOS3-/- compared with WT mice at E10.5 and E12.5. Finally, in the adult aortic valves, NOS3 is important in inhibition of thrombosis formation. Deficiency in NOS3 leads to aortic valve thrombosis and calcification. At 12 months old, 72% (13/18) of NOS3-/- mice showed severe spontaneous aortic valve thrombosis compared with WT mice (0/12). Ex vivo culture of aortic valves showed that platelet aggregation and adhesion were significantly increased in NOS3-/- aortic valves compared with WT aortic valves. There was also a significant regurgitation of the aortic valve during systole in the NOS3-/- compared with WT mice. In addition, NOS3 deficiency resulted in significant aortic valve stenosis, calcification and fibrosis. In summary, these data suggest NOS3 plays a critical role in embryonic heart development and morphogenesis of coronary arteries and inhibits thrombosis formation in the adult aortic valves.

Heart disease is the leading cause of death in the world. Therefore, numerous studies are undertaken to identify indicators which can be applied to discover cardiac dysfunctions at an early age. Among others, the fluid dynamics of the blood flow (hemodymanics) is considered to contain relevant information related to abnormal performance of the heart.This thesis presents a robust framework for numerical simulation of the fluid dynamics of the blood flow in the left ventricle of a human heart and the fluid-structure interaction of the blood and the aortic leaflets.We first describe a patient-specific model for simulating the intraventricular blood flow. The motion of the endocardial wall is extracted from data acquired with medical imaging and we use the incompressible Navier-Stokes equations to model the hemodynamics within the chamber. We set boundary conditions to model the opening and closing of the mitral and aortic valves respectively, and we apply a stabilized Arbitrary Lagrangian-Eulerian (ALE) space-time finite element method to simulate the blood flow. Even though it is difficult to collect in-vivo data for validation, the available data and results from other simulation models indicate that our approach possesses the potential and capability to provide relevant information about the intraventricular blood flow.To further demonstrate the robustness and clinical feasibility of our model, a semi-automatic pathway from 4D cardiac ultrasound imaging to patient-specific simulation of the blood flow in the left ventricle is developed. The outcome is promising and further simulations and analysis of large data sets are planned.In order to enhance our solver by introducing additional features, the fluid solver is extended by embedding different geometrical prototypes of both a native and a mechanical aortic valve in the outflow area of the left ventricle.Both, the contact as well as the fluid-structure interaction, are modeled as a unified continuum problem using conservation laws for mass and momentum. To use this ansatz for simulating the valvular dynamics is unique and has the expedient properties that the whole problem can be described with partial different equations and the same numerical methods for discretization are applicable.All algorithms are implemented in the high performance computing branch of Unicorn, which is part of the open source software framework FEniCS-HPC. The strong advantage of implementing the solvers in an open source software is the accessibility and reproducibility of the results which enhance the prospects of developing a method with clinical relevance. / <p>QC 20171006</p>