Congenital heart valve disease is one of the most common abnormalities in children, with common valve defects being aortic stenosis, mitral stenosis, and valvular regurgitation. Although adult sized mechanical heart valve (MHV) replacements are widely studied and utilized, there are currently no FDA approved prosthetic heart valves available for the pediatric population. This is due to a variety of reasons such as a limited patient pool for clinical trials, limited valve sizes, and complex health histories in children. Much like adult sized mechanical heart valves, potential complications with pediatric heart valve replacements include thrombosis, blood damage due to high shear stresses, and cavitation. Due to pediatric sized MHVs being much smaller in size than adult MHVs, different fluid dynamic conditions and associated complications are expected. In order to accelerate the approval of pediatric sized heart valves for clinical use, it is important to first characterize and assess the fluid dynamics across pediatric sized heart valves. By understanding the hemodynamic performance of the valve, connections can be made concerning potential valve complications such as thrombosis and cavitation. The overall objective of this study is to better characterize and assess the flow field characteristics of a pediatric sized mechanical heart valve using flow visualization techniques in a mock circulatory loop. The mechanical heart valve chosen for this research was a size 17 mm Bjork-Shiley tilting disc valve, as this is a common size valve used for younger patients with smaller cardiovascular anatomy. The mock circulatory loop used in this research was designed to provide realistic pediatric physiological flow conditions, consisting of a Harvard Apparatus Pulsatile blood pump, venous reservoir, and a heart valve testing chamber. In order to expose the valve to realistic pediatric flow conditions, six unique pump operating conditions were tested that involved pre-determined heart rate and stroke volume combinations. In addition, a modified aortic root model was used to hold the mechanical heart valve in place within the loop and to provide more realistic aortic root geometry. This heart valve chamber was made from a transparent acrylic material, allowing for fluid flow visualization. A traditional Particle Image Velocimetry (PIV) experimental set up was used in order to illuminate the particles seeded within the fluid path, and thus allowing for the capture of sequential images using a high speed camera. The data collected throughout this study consisted of flow rate measurements using an ultrasonic flow meter, and the sequential PIV images obtained from the camera in order to analyze general flow characteristics across the pediatric valve. Such information regarding the flow profile across the valve allowed for conclusions to be made regarding the valve performance, such as average flow velocities and regions of regurgitant flow. By gaining a better understanding of the fluid dynamic profile across a pediatric sized heart valve, this may aid in the eventual approval of pediatric sized mechanical heart valves for future clinical use.

Background Every year about 2,500 patients in Sweden undergo surgery for heart valve disease, primarily in the aortic valve.  In contrast to the mitral valve, which can be repaired in 70% of the cases, the aortic valve is normally replaced by a mechanical or biological prosthesis. A mechanical heart valve (MHV) necessitates lifelong anticoagulation treatment with a vitamin K antagonist, most commonly warfarin, due to the high thrombogenicity of the prosthesis. The quality of the warfarin treatment is crucial in these patients. Compared to other countries, treatment quality in Sweden is very high; nonetheless, there is always room for improvement. One of the ways to achieve this improvement is to implement computerized dosing assistance. Treatment recommendations for anticoagulation intensity are based on few and old studies, making these recommendations uncertain. There is therefore a need for studies designed to establish the appropriate level of anticoagulation therapy. Aim The aim of these studies was to investigate the efficacy and safety of anticoagulation treatment among patients with mechanical heart valve prostheses in Sweden; to assess whether computerized dosing can increase the treatment quality; to investigate the influence of the treatment quality, measured by Time in Therapeutic Range (TTR) and INR variability, on the risk of complications and, finally, to establish the optimal intensity of anticoagulation treatment in this group of patients. Methods Data were obtained from AuriculA – a national quality registry established in 2006, which currently includes approximately 50% of all patients treated with oral anticoagulation in Sweden. Study II used only data from AuriculA. 769,933 warfarin-dosing suggestions proposed by the dosing algorithm in AuriculA were analysed. Accepted dose suggestions (590,939) were compared with 178,994 manually-changed doses in regard to the resultant INR value, measured as mean error (deviation from target INR) and hit rate (number of INR samples within the target range 2-3). In study III, AuriculA was used to identify patients in Sundsvall and Malmö in the period 2008 – 2011 who were receiving warfarin for a mechanical heart valve prosthesis, as well as to retrieve their INR data. Data on background characteristics and bleedings or thromboembolic complications were manually retrieved from medical records by two investigators.  A total of 534 patients with mechanical heart valve prostheses were divided into quartiles based on TTR and were compared regarding the risk of complications. For Studies I and IV, data from AuriculA were merged with the Swedish National Patient Register, SWEDEHEART/ Heart surgery, and the Swedish Cause of Death Register, comprising in total 77,423 patients on warfarin with 217,804 treatment years. Every treatment period registered in AuriculA was given an individual identification number. During the study period a patient could have any number of treatment periods. The number of complications in total and in different patient groups within the study population was investigated. Complications were defined by ICD-10 codes. Major bleeding was defined as an event necessitating hospital treatment and given a discharge diagnosis with one of the ICD-10 codes reflecting bleeding, as listed in the Appendix. Bleeding events were divided into intracranial, gastrointestinal and other bleedings. Thromboembolic complications consist of venous events (deep vein thrombosis, pulmonary embolism, venous stroke) or arterial events (stroke, TIA, acute myocardial infarction, peripheral arterial embolism). Data were analysed using both simple, descriptive statistical methods and various tests such as Mann-Whitney (or two sample Wilcoxon), T-test, Chi 2 test, ANOVA, multivariate analysis with logistic regression and survival analysis with Cox Regression with proportional hazard assumption. Results Treatment quality  Mean TTR among all patients in Study I was 76.5% whereas patients with mechanical heart valve prostheses had a TTR of 74.5%. The annual incidence of major bleeding or thromboembolic events among all patients was 2.24% and 2.65%, respectively. The incidence of intracranial bleeding was 0.37% per year in the general population and 0.51% among patients with mechanical heart valve prostheses, who also had a higher bleeding rate in total (3.37% per year). Both the mean and median errors were smaller (0.44 vs. 0.48 and 0.3 vs. 0.4, respectively) and the hit rate was higher (0.72 vs. 0.67) when the dose suggested by the algorithm was accepted, compared to when it was manually changed. TTR  In Study III there was no significant difference in the risk of thromboembolism regardless of TTR level. Risk of bleeding in quartiles I and II was more than two times higher than in the quartile with TTR >82.9. In Study IV, lower TTR (≤70%) was associated with a significantly higher rate of complications when compared with TTR >70%. Bleeding risk was higher in the group with lower TTR (HR=2.43, CI 2.02-2.89, p<0.001). After dividing patients into TTR quartiles, the rate of complications in total was significantly higher in quartiles I to III compared with quartile IV, which had the highest TTR. Risk of thromboembolism, major bleeding and death was higher in the first and second quartile compared to the quartile with the highest TTR. INR variability  Higher INR variability above mean (≥0.40) was related to a higher rate of complications compared with lower INR variability (<0.40) as shown in Study IV. Bleeding risk was higher in the group with INR variability ≥0.40 (HR = 2.15, CI 1.75-2.61, p<0.001). Comparison of quartile IV, which had the lowest INR variability, with the other three revealed that quartiles I and II, which had the highest INR variability, had significantly worse outcomes for all complications except for thromboembolic events, plus also death in quartile II. TTR and INR variability combined  High variability and low TTR combined was associated with a higher risk of bleedings (HR 2.50, CI 1.99-3.15), death (3.34, CI 2.62-4-27) and thrombosis (1.55, CI 1.21-1.99) compared to the best group. Level of anticoagulation Higher warfarin treatment intensity (mean INR 2.8-3.2 vs. 2.2-2.7) was associated with a higher rate of bleedings (HR 1.29, CI 1.06-1.58), death (1.73, CI 1.38-2.16) and complications in total (1.24, CI 1.06-1.41) after adjustment for MHV position, age and comorbidity. Conclusion Warfarin treatment quality is crucial for patients with mechanical heart valve prostheses. Computerized dosing assistance could help maintain high warfarin treatment quality. Well-managed treatment with TTR ≥70% and INR variability below mean <0.40 is associated with a lower risk of serious complications compared with a lower TTR and higher INR variability. No benefit of higher warfarin treatment intensity was found for any valve type or position.

A major drawback in the operation of mechanical heart valve prostheses is thrombus formation in the near valve region potentially due to the high shear stresses present in the leakage jet flows through small gaps between leaflets and the valve housing. Detailed flow analysis in this region during the valve closure phase is of interest in understanding the relationship between shear stress and platelet activation. An efficient Cartesian grid method is developed for the simulation of incompressible flows around stationary and moving three-dimensional immersed solid bodies as well as fluid-fluid interfaces. The embedded boundaries are represented using Levelsets and treated in a sharp manner without the use of source terms to represent boundary effects. The resulting algorithm is implemented in a straightforward manner in three dimensions and retains global second-order accuracy. When dealing with problems of disparate length scales encountered in many applications, it is necessary to resolve the physically important length scales adequately to ensure accuracy of the solution. Fixed grid methods often have the disadvantage of heavy mesh requirement for well resolved calculations. A quadtree based adaptive local mesh refinement scheme is developed to complement the sharp interface Cartesian grid method scheme for efficient and optimized calculations. Detailed timing and accuracy data is presented for a variety of benchmark problems involving moving boundaries. The above method is then applied to modeling heart valve closure and predicting thrombus formation. Leaflet motion is calculated dynamically based on the fluid forces acting on it employing a fluid-structure interaction algorithm. Platelets are modeled and tracked as point particles by a Lagrangian particle tracking method which incorporates the hemodynamic forces on the particles. Leaflet closure dynamics including rebound is analyzed and validated against previous studies. Vortex shedding and formation of recirculation regions are observed downstream of the valve, particularly in the gap between the valve and the housing. Particle exposure to high shear and entrapment in recirculation regions with high residence time in the vicinity of the valve are observed corresponding to regions prone to thrombus formation.

A number of clinical, in vitro and computational studies have shown the potential for thromboembolic complications in bileaflet mechanical heart valves (BMHV), primarily due to the complex and unsteady flows in the valve hinges. These studies have focused on quantitative and qualitative parameters such as velocity magnitude, turbulent shear stresses, vortex formation and platelet activation to identify potential for blood damage. However, experimental characterization of the whole flow fields within the valve hinges has not yet been conducted. This information can be utilized to investigate instantaneous damage to blood elements and also to validate numerical studies focusing on the hinge’s complex fluid dynamics. The objective of this study was therefore to develop a high-resolution imaging system to characterize the flow fields and global velocity maps in a BMHV hinge. Subsequently, the present study investigated the effect of hinge gap width on flow fields in a St. Jude Medical BMHV. The results from this study suggest that the BMHV hinge design is a delicate balance between reduction of fluid shear stresses and areas of flow stasis during leakage flow, and needs to be optimized to ensure minimal thromboembolic complications. Overall, the current study demonstrates the ability of high-resolution Micro Particle Image Velocimetry to assess the fluid flow fields within the hinges of bileaflet mechanical heart valves, which can be extended to investigate micro-scale flow domains in critical regions of other cardiovascular devices to assess their blood damage potential.

The tendency of aortic bileaflet mechanical heart valves (BiMHVs) to promote thrombosis has been well documented in the literature. The relationship of thrombosis to valve fluid dynamics has prompted numerous studies of aortic BiMHV flow. In this study, steady flow was investigated downstream of a model Carbomedics No. 25 BiMHV in an axisymmetric aortic sinus using stereoscopic particle image velocimetry (SPIV). The Reynolds number based on inlet diameter was 7600, and the measurement plane was perpendicular to the leaflet axes at the centerline of the aortic sinus. The typical formation of three jets was observed: the upper and lower lateral orifice jets, and the central jet. Flow separation from the valve ring was seen, and large scale vortices were identified in both the upper and lower sinus regions. An asymmetry in the reverse flow was found, and possible causes were discussed. All three jets were seen to decay similarly to free rectangular jets, with zero decay initially, followed by a 'linear' decay rate in which Umax^2~X. The central jet was also seen to be self similar in the linear decay region. Analysis of the out-of-plane velocity yielded two alternate explanations of streamwise vortex (i.e. Wx) structure, with either a four-cell or an eight-cell streamwise vortex structure being present in the mean velocity field. Organization of large scale three dimensional flow structures was thus apparent. Calculation of in-plane Reynolds stresses showed that values were highest in the outer shear layers of the lateral orifice jets. Elevated Reynolds shear stress values were also found in the leaflet wake regions, and the shear layers of the central jet.

The tendency of aortic bileaflet mechanical heart valves (BiMHVs) to promote thrombosis has been well documented in the literature. The relationship of thrombosis to valve fluid dynamics has prompted numerous studies of aortic BiMHV flow. In this study, steady flow was investigated downstream of a model Carbomedics No. 25 BiMHV in an axisymmetric aortic sinus using stereoscopic particle image velocimetry (SPIV). The Reynolds number based on inlet diameter was 7600, and the measurement plane was perpendicular to the leaflet axes at the centerline of the aortic sinus. The typical formation of three jets was observed: the upper and lower lateral orifice jets, and the central jet. Flow separation from the valve ring was seen, and large scale vortices were identified in both the upper and lower sinus regions. An asymmetry in the reverse flow was found, and possible causes were discussed. All three jets were seen to decay similarly to free rectangular jets, with zero decay initially, followed by a 'linear' decay rate in which Umax^2~X. The central jet was also seen to be self similar in the linear decay region. Analysis of the out-of-plane velocity yielded two alternate explanations of streamwise vortex (i.e. Wx) structure, with either a four-cell or an eight-cell streamwise vortex structure being present in the mean velocity field. Organization of large scale three dimensional flow structures was thus apparent. Calculation of in-plane Reynolds stresses showed that values were highest in the outer shear layers of the lateral orifice jets. Elevated Reynolds shear stress values were also found in the leaflet wake regions, and the shear layers of the central jet.

The presented thesis solves a flow through the artificial heart valves. The thesis concerns with a historic development of mechanical heart valves and their basic parameters. It also includes a short research about Dynamic mesh module, which is contained within ANSYS Fluent. An experiment with a real mechanical heart valve was done within the diploma thesis and obtained data were compared with physiological ones. One part of this work was a design of 3D model of real heart valve replacement. The model was used for fluid dynamic computations using the Dynamic mesh of ANSYS Fluent software. In the end are the results of experimental part and numerical solutions used for few suggestions that could improve the function of the artificial heart valve.

Patients with mechanical heart valves who present with intracranial haemorrhage are initially treated by reversing their coagulopathy. However, these patients will ultimately require that their oral anticoagulant be restarted. The time at which oral anticoagulants are restarted is critical since restarting too early may increase the risk of recurrent bleeding, while withholding anticoagulants increases the patient’s risk of thromboembolic events. The ideal time to restart patients on their oral anticoagulant medication is defined as the time at which all these risks are minimized. This thesis includes a systematic review and meta-analysis of the literature. The main outcomes were recurrent haematoma, valve thrombosis, stroke and peripheral emboli. Results were stratified by types of intracranial haemorrhage. We also conducted a survey to gain insight into current practices of neurosurgeons and thrombosis experts in Canada and USA when they are faced with deciding on anticoagulant restart times in patients with ICH. Results were stratified by type of intracranial bleed and participants’ characteristics and demographics. The systematic review identified that the ideal time for restarting anticoagulant therapy in patients following an ICH is unknown. Meta-analysis was limited by the heterogeneity of the studies. The survey results indicated that physicians had a wide range of practice and that their practice was dependent on the patient’s clinical features, but many physicians would restart oral anticoagulants between 4 and 14 days after the haemorrhage. For this reason we have proposed a multi centre cohort study to investigate the safety and efficacy of restarting patients on anticoagulation therapy between day 5 and 9 post haemorrhage. A full study protocol is presented in this thesis.

Patients with mechanical heart valves who present with intracranial haemorrhage are initially treated by reversing their coagulopathy. However, these patients will ultimately require that their oral anticoagulant be restarted. The time at which oral anticoagulants are restarted is critical since restarting too early may increase the risk of recurrent bleeding, while withholding anticoagulants increases the patient’s risk of thromboembolic events. The ideal time to restart patients on their oral anticoagulant medication is defined as the time at which all these risks are minimized. This thesis includes a systematic review and meta-analysis of the literature. The main outcomes were recurrent haematoma, valve thrombosis, stroke and peripheral emboli. Results were stratified by types of intracranial haemorrhage. We also conducted a survey to gain insight into current practices of neurosurgeons and thrombosis experts in Canada and USA when they are faced with deciding on anticoagulant restart times in patients with ICH. Results were stratified by type of intracranial bleed and participants’ characteristics and demographics. The systematic review identified that the ideal time for restarting anticoagulant therapy in patients following an ICH is unknown. Meta-analysis was limited by the heterogeneity of the studies. The survey results indicated that physicians had a wide range of practice and that their practice was dependent on the patient’s clinical features, but many physicians would restart oral anticoagulants between 4 and 14 days after the haemorrhage. For this reason we have proposed a multi centre cohort study to investigate the safety and efficacy of restarting patients on anticoagulation therapy between day 5 and 9 post haemorrhage. A full study protocol is presented in this thesis.

Patients with mechanical heart valves who present with intracranial haemorrhage are initially treated by reversing their coagulopathy. However, these patients will ultimately require that their oral anticoagulant be restarted. The time at which oral anticoagulants are restarted is critical since restarting too early may increase the risk of recurrent bleeding, while withholding anticoagulants increases the patient’s risk of thromboembolic events. The ideal time to restart patients on their oral anticoagulant medication is defined as the time at which all these risks are minimized. This thesis includes a systematic review and meta-analysis of the literature. The main outcomes were recurrent haematoma, valve thrombosis, stroke and peripheral emboli. Results were stratified by types of intracranial haemorrhage. We also conducted a survey to gain insight into current practices of neurosurgeons and thrombosis experts in Canada and USA when they are faced with deciding on anticoagulant restart times in patients with ICH. Results were stratified by type of intracranial bleed and participants’ characteristics and demographics. The systematic review identified that the ideal time for restarting anticoagulant therapy in patients following an ICH is unknown. Meta-analysis was limited by the heterogeneity of the studies. The survey results indicated that physicians had a wide range of practice and that their practice was dependent on the patient’s clinical features, but many physicians would restart oral anticoagulants between 4 and 14 days after the haemorrhage. For this reason we have proposed a multi centre cohort study to investigate the safety and efficacy of restarting patients on anticoagulation therapy between day 5 and 9 post haemorrhage. A full study protocol is presented in this thesis.