Introdução: A apnéia central do sono e a apnéia obstrutiva do sono (ACS e AOS, respectivamente) são comuns em pacientes com insuficiência cardíaca com disfunção sistólica (ICC). No entanto, vários fatores que levam a instabilidade respiratória incluindo baixo débito cardíaco, congestão pulmonar e hipocapnia coexistem nestes pacientes. Pacientes com valvopatias (VAL) com alta pressão de capilar pulmonar (PCP) e com fração de ejeção (FE) de ventrículo esquerdo normal representam um modelo adequado para elucidar a gênese da apnéia do sono. Objetivos: Comparar as características dos distúrbios respiratórios do sono em pacientes com VAL e pacientes com ICC. Métodos: Pacientes com VAL com PCP > 12 mmHg e pacientes com ICC foram avaliados por, gasometria arterial, ecocardiograma e polissonografia. Resultados: Pacientes com VAL (n=17, PCP 24 ± 9 mmHg e FE 61 ± 6 %) e ICC (n=17, FE 31 ± 10 %) eram semelhantes quanto as características demográficas e gases arteriais (idade: 46 ± 10 versus 47 ± 9, sexo feminino: 11 em ambos os grupos, índice de massa corporal: 26 ± 5 vs 26 ± 6 Kg/m2, PaCO2: 34 ± 3 vs 35 ± 4 mmHg, respectivamente). Pacientes com VAL apresentaram índice de apnéia-hipopnéia (IAH) significativamente menor do que pacientes com ICC (10 ± 8 e 26 ± 25 eventos/hora, p=0,0179) e uma menor prevalência de apnéia do sono (IAH > 15 eventos/hora, 29% e 53%, p=0,0009). Dentre os pacientes com apnéia do sono, os pacientes com VAL apresentaram predominantemente AOS (60%) enquanto os pacientes com ICC apresentaram predominantemente ACS (89%, p < 0,0001). Conclusões: Pacientes com VAL e alta PCP e FE normal apresentam apnéia do sono menos grave e com excesso de eventos de origem obstrutiva quando comparados com pacientes com ICC. Congestão pulmonar e hipocapnia não explicam completamente a presença de ACS em pacientes com doenças cardíacas / Introduction: Central and obstructive sleep apnea (CSA and OSA, respectively) are common in patients with systolic congestive heart failure (ICC). However, several factors leading to respiratory instability, including low cardiac output, pulmonary congestion and hypocapnia co-exist in these patients. Patients with valvular heart disease (VAL) with high pulmonary capillary wedge pressure (PCWP) but normal resting left ventricular ejection fraction (LVEF) may provide insights into the genesis of sleep apnea. Objectives: Compare sleep disordered breathing characteristics in patients with VAL and patients with ICC. Methods: Patients with VAL and PCWP > 12 mmHg and ICC were evaluated by awake arterial blood gas analysis, echocardiogram and overnight polysomnography. Results: Patients with VAL (n=17, PCP=24 ± 9 mmHg and LVEF=61 ± 6 %) and ICC (n=17, LVEF=31 ± 10 %) were similar for demographics and blood gases (age: 46 ± 10 vs 47 ± 9, females: 11 in both groups, body mass index: 26 ± 5 Kg/m2 vs 26 ± 6, PaCO2: 34 ± 3 vs 35 ± 4 mmHg, respectively). Patients with VAL as compared to patients with ICC presented significantly lower apnea hypopnea index (10 ± 8 vs 26 ± 25 events/hour, p=0.0179), a lower prevalence of sleep apnea (apnea-hypopnea index > 15 events/hour) 29% vs 53%, p=0.0009, and among patients with sleep apnea the nature was predominantly OSA (60%) while patients with ICC had predominantly CSA (89%, p < 0.0001). Conclusion: Patients with VAL and high PCWP had a less severe sleep apnea and an excess of obstructive events when compared to patients ICC. Pulmonary congestion and hypocapnia do not completely explain CSA in patients with heart diseases

Cette étude à pour but de développer un concept de stent atraumatique pour le remplacement percutanée de la valve aortique. Le stent est obtenu à partir de brins de Nitinol tressés, ce qui lui permet, de part sa géométrie et sa structure, d'être compressible, auto-expansible, et atraumatique. Le principe de fabrication des prototypes et les contraintes qui lui est associé sont présentées. Les performances de ces prototypes, en terme d'ancrage, de régurgitation statique et de régurgitation dynamique sont ensuite évaluées par des essais in vitro, pour lesquel le banc de test en flux pulsé a été optimisé afin de prendre en considération la compliance de la racine aortique. Les résultats obtenus permettent de mettre en évidence les différents paramètres de fabrication stent, tant au niveau dimensionnel (hauteur du cylindre, angle du cône...) qu'au niveau structurel (rigidité), qui ont une influence significative sur le comportement de l'endoprothèse. / The goal of this work is to develop an atraumatic stent concept for percutaneous aortic valve replacement. Shape setted braided nitinol wires, thanks to their specific geometry and elasticity, allows stent's compressibility, self deployment and aortic root preservation. Prototypes manufacturing technique and relatives constraints are presented. Performance of the obtained prototypes are evaluated in vitro, in terms of sealing, static and dynamic regurgitation. More specifically, the pulsatile bench testing has been optimized to take in account the compliant constraint of the aortic valve environment. The results bring to the fore which are the dimensions (head height, cone angle...) and the structures features that do influence the endoprosthesis behavior significantly.

Novel biomaterials provide a spectrum of possibilities. They can be engineered in different forms to understand how they would perform as different bioprosthetic conduits. Bacterial cellulose membranes may be suitable candidates as prosthetic valve leaflets in valve replacement surgeries due to their functional properties (hemodynamics, resistant to thrombosis). Biomaterials used for most bioprosthetic heart valves are cut, trimmed and sutured. A major challenge for the bi-leaflet configuration is that the cutting and suturing of biopolymers fabricated as sheets into a cylindrical form increases failure risk due to greater number of suture points and irregular coaptation. The objective was to culture the bacterial cellulose membrane as a continuous cylindrical construct and evaluate its mechanical properties. Various design features of the fabrication process such as culturing media and the hollow carrier-mandrel characteristics were evaluated. A comparative study of how bacterial cellulose grows on different hollow carrier membranes was conducted and thin smooth surface silicone tubes fabricated in the lab were found to be most suitable. A bioreactor for culturing cylindrical bacterial cellulose tubes on the outer surface of the hollow carrier was designed and fabricated. The mechanical properties of the fabricated tubes, specifically, their tensile strength, flexure, suture retention and tear resistance were characterized. Mechanical characterization studies showed the cylindrical bacterial cellulose tubes to be anisotropic, with preferential properties in the longitudinal (axial) direction of the tube. Preliminary results show that cylindrical bacterial cellulose tubes can be a promising candidate for use in prosthetic valve conduits.

<p>A more global analysis of the outcome of heart valve surgery is desirable to reflect the actual benefit for the patient. This thesis focuses on the preoperative assessment of the patient, and the outcome after surgery with regard to operative mortality, long-term survival, valve-related complications, and quality of life. </p><p>Magnetic resonance imaging and echocardiography were comparable in assessing severe mitral regurgitation, but did not agree in measuring regurgitant fraction. Natriuretic peptides correlated well to regurgitant fraction on magnetic resonance imaging and to PISA and vena contracta on echocardiography. </p><p>The risk of death, myocardial injury and postoperative heart failure after valve surgery has decreased over the last decade whereas the proportion older patients has increased. </p><p>Survival is reduced after mitral valve replacement in patients with severe symptoms whereas patients with less symptoms have excellent survival. Older patients are more often severly symptomatic at the time of mitral valve surgery. </p><p>Event-free survival is superior in patients with a mechanical prosthesis, but not influenced by valve type in older patients. A mechanical prosthesis is associated with a higher risk of bleeding < 5 years from surgery, especially in older patients; and a bioprosthesis is associated with a higher risk of thromboembolism > 5 years from surgery. Ageing with a mechanical prosthesis implied an increased risk for an adverse event, this was not true for bioprostheses. </p><p>Quality of life after complicated heart valve surgery resulted in reduced physical health but equal mental health compared to uncomplicated controls.</p>

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.

A more global analysis of the outcome of heart valve surgery is desirable to reflect the actual benefit for the patient. This thesis focuses on the preoperative assessment of the patient, and the outcome after surgery with regard to operative mortality, long-term survival, valve-related complications, and quality of life. Magnetic resonance imaging and echocardiography were comparable in assessing severe mitral regurgitation, but did not agree in measuring regurgitant fraction. Natriuretic peptides correlated well to regurgitant fraction on magnetic resonance imaging and to PISA and vena contracta on echocardiography. The risk of death, myocardial injury and postoperative heart failure after valve surgery has decreased over the last decade whereas the proportion older patients has increased. Survival is reduced after mitral valve replacement in patients with severe symptoms whereas patients with less symptoms have excellent survival. Older patients are more often severly symptomatic at the time of mitral valve surgery. Event-free survival is superior in patients with a mechanical prosthesis, but not influenced by valve type in older patients. A mechanical prosthesis is associated with a higher risk of bleeding &lt; 5 years from surgery, especially in older patients; and a bioprosthesis is associated with a higher risk of thromboembolism &gt; 5 years from surgery. Ageing with a mechanical prosthesis implied an increased risk for an adverse event, this was not true for bioprostheses. Quality of life after complicated heart valve surgery resulted in reduced physical health but equal mental health compared to uncomplicated controls.

Currently, mitral valve repair techniques have shown substandard mid-term and long term results. In order to improve the efficacy of these repair techniques, detailed knowledge of normal mitral valve function and the alterations to the valvular and subvalvular apparatus which occur under pathological conditions is required. Furthermore, current techniques may be optimized through a better understanding of the function and mechanics of the mitral valve after a particular repair. The experiments which comprise this study were designed using an in vitro approach since this technique has the clear advantage of isolating and independently controlling specific parameters that are of importance to valvular mechanics and function. The experiments were conducted in the Georgia Tech Left Heart Simulator using native porcine and human mitral valves. The first set of experiments measured the chordal force distribution and anterior leaflet strain of the mitral valve in its normal geometrical configuration. Subsequent experiments measure mitral regurgitation volume and chordal force distribution in conditions associated with ventricular dilation. The last set of experiments simulated two commonly used mitral repair techniques. For the Alfieri stitch experiments, the effects of mitral flow rate, transmitral pressure, and mitral annular area on valve stenosis, mitral regurgitation and Alfieri stitch force were evaluated. For annuloplasty, the effect of annular saddle curvature on anterior leaflet strain was quantified. In Conclusion, the normal geometry of the native mitral valve optimized its function and mechanics. Under pathological conditions associated with ventricular dilation, significant alterations to mitral valve function and mechanics were present. Although the studied repair techniques may have significantly restored valve function, severe alterations to the mechanics of the valve still persisted.

Bileaflet mechanical heart valves (BMHVs), though a life-saving tool in treating heart valve disease, are often associated with serious complications, including a high risk of hemolysis, platelet activation, and thromboembolism. One likely cause of this hyper-coagulative state is the nonphysiologic levels of stress experienced by the erythrocytes and platelets flowing through the BMHVs. Research has shown that the combination of shear stress magnitude and exposure time found in the highly transient leakage jet emanating from the b-datum gap during valve closure is sufficient to cause hemolysis and platelet activation. Regions of flow stasis in the valve vicinity may also allow activated platelets to aggregate and form thrombus. This thesis addresses the hypothesis that passive flow control may have the potential to reduce flow-induced thrombogenicity by altering the fluid mechanics of bileaflet mechanical heart valves. To test this hypothesis, a steady model of the regurgitant b-datum line jet was developed and studied. This model served as a test bed for various vortex generator array designs. The fluid mechanics of the b-datum line jet model was investigated with flow visualization and particle image velocimetry. In vitro tests with whole human blood were performed with and without the vortex generators in order to determine how the presence of the passive flow control affected the propensity of the blood to form thrombus. An effort was then made to correlate the fluid mechanics of the jet model with the procoagulant potential results from the blood experiments. The effect of the vortex generators on the fluid mechanics of the valve under physiologic pulsatile conditions was also investigated via flow visualization in the Georgia Tech Left Heart Simulator. By studying a steady model of the regurgitant b-datum line jet, it was found, using an in vitro system with whole human blood, that the presence of vortex generators significantly decreased the blood's propensity for thrombus formation. The potential of applying passive flow control to cardiovascular hardware in order to mitigate the injurious effects of shear-induced platelet activation is thus demonstrated. The investigation into the effect of vortex generators on the fluid mechanics of the b-datum line jet showed that the jet oscillated aperiodically and that the effect of the applied flow control was played out at both the scale of the chamber (large-scale) and on the scale of the vortex generator fins (small-scale). On the large scale, the presence of vortex generators appeared to decrease the magnitude or frequency of jet oscillation, thereby stabilizing the jet. After removing the effect of the large-scale oscillations via phase averaging, the effect of the vortex generators on the small scale was examined. On the small scale, the jet without flow control was found to have higher levels of velocity RMS, particularly on the jet periphery, and higher levels of Reynolds shear stress. It is proposed that the vortex generators effect this change by generating vorticity in the plane of the jet. This vorticity is theorized to stabilize the jet, delaying roll-up of the jet shear layer which occurs via the Kelvin-Helmholtz instability. The method by which the vortex generators acted on the fluid mechanics of the steady jet system to decrease the blood's procoagulant potential was investigated via flow visualization and DPIV. The results from these studies implicate two possible mechanisms by which the vortex generators may act. First, the peak turbulent shear stresses in the jet were reduced by 10-20% with the application of vortex generators. Even if only a few platelets were activated in each passage through the valve, the cumulative effect of this difference in peak stresses after many passes would be greatly magnified. Thus, this reduction in turbulent shear stresses may be sufficient to explain the change seen in the blood's procoagulant potential with the application of passive flow control. It is suspected, though, that the second mechanism is dominant. The flow fields revealed that the presence of the vortex generators delayed or prevented the roll-up of the Kelvin-Helmholtz instability in the b-datum jet's shear layers into discrete vortices. By doing so, it is thought that opportunities for the interaction of activated and unactivated platelets entrained in these vortices were prevented, thereby inhibiting further propagation of the coagulation cascade. Even if the rate at which platelets were activated was similar for cases with and without flow control, it seems that the flow fields experienced by the platelets subsequent to activation can determine the level of procoagulant potential. Under the steady conditions observed in this experiment, the jet influenced by vortex generators was thus shown to induce significantly lower levels of procoagulant potential.

Calcific aortic valve disease (CAVD) is associated with significant cardiovascular morbidity. While late-stage valve disease is well-described, there remains an unmet scientific need to elucidate early pathobiological processes. In CAVD, pathological differentiation of valvular interstitial cells (VICs) and lesion formation occur focally in the fibrosa layer. This VIC pathological differentiation has been shown to be influenced by matrix stiffness in vitro. However, little is known about the focal layer specific mechanical properties of the aortic valve in health and disease and how these changes in matrix moduli may influence VIC pathological differentiation in vivo. In this thesis, micropipette aspiration (MA) was shown to be capable of measuring the mechanical properties of a single layer in multilayered biomaterial or tissue such as the aortic valve, if the pipette inner diameter was less than the top layer thickness. With MA, the fibrosa of normal porcine aortic valves was significantly stiffer than the ventricularis; stiffer locations found only within the fibrosa were comparable to stiffnesses shown in vitro to be permissive to VIC pathological differentiation. Early CAVD was induced in a porcine model, which developed human-like early CAVD lesion onlays. Extracellular matrix remodeling occurred in the absence of lipid deposition, macrophages, osteoblasts, or myofibroblasts, but with significant proteoglycan-rich onlays and chondrogenic cell presence. These early onlays were softer than the collagen-rich normal fibrosa, and their proteoglycan content was positively correlated with Sox9 chondrogenic expression, suggesting that soft proteoglycan-rich matrix may be permissive to chondrogenic VIC differentiation. The findings from this thesis shed new light on early disease pathogenesis and improve the fundamental understanding of aortic valve mechanics in health and disease.

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.