<p> A stress analysis of porcine aortic valve leaflets in diastole at 80 mm. Hg. in-vitro is presented. Incorporations of local surface geometry, leaflet material inhomogeneity, anisotropy and non-linearity are applied. The stress theory used is a modified form of the thin membrane stress theory for a homogeneous, linearly elastic and orthotropic lamina. Modifications are made so that the linear Hooke's Law equations of stress may be applied to the inhomogeneous, non-linearly elastic and orthotropic thin membrane aortic valve leaflets. </p> <p> Stress calculations are made on the premise that the diastolic valve leaflets at 80 mm. Hg. are in pre-transition (that is, characterized by a small elastic modulus) for the circumferential direction, and in post-transition (that is, characterized by a large elastic modulus) for the radial direction. Circumferential stresses are calculated to be relatively negligible; they are estimated to be less than 1 gm/mm². Radial stresses for the non coronary leaflet lie primarily in the 0 to 20 gm/mm² range. The regions of the largest stress concentrations are in the areas of mutual leaflet coaptation, especially near the Nodes of Aranti. A progressive increase of the radial stresses from the sinus annulus edges toward the coaptation edges of the leaflets is also observed. Based on the one valve reported , it appears that the left coronary leaflet is the highest stressed and the right coronary leaflet is the least stressed. Central leaflet radial stresses for the right coronary leaflet are in the 0 to 10 gm/mm² range, as compared to 0 to 20 gm/mm² for the non coronary and left coronary leaflets. </p> <p> The question as to whether the diastolic strains of the valve leaflets are in pre-transition, transition or post-transition is raised. The resolution of the question is seen to be critical to the validity of the stress analysis. It is also realized that further improvements in the analysis are possible through improvements and refinements to the experimental methods used in obtaining the necessary inputs for the analysis. </p> / Thesis / Master of Engineering (ME)

Aortic valve replacement (AVR) is the only life-saving treatment for patients with severe symptomatic aortic stenosis. Bioprosthetic valves are used in 90% of AVRs because they do not require lifelong anticoagulation. The major limitation of bioprosthetic valves is their limited durability compared to mechanical valves. In addition, bioprosthetic valves still carry a 2-3% risk of symptomatic valve thrombosis, stroke, and thromboembolism in the first 30 days after implantation, and a 1% annual risk thereafter. The risk of subclinical valve thrombosis is around 10% at 30 days and 25% at 1 year, and prevention of subclinical valve thrombosis is hypothesized to reduce the risk of clinical thrombotic events and perhaps even improve valve durability, although high-quality evidence is lacking. This doctoral thesis comprises 7 chapters of varied methodology that summarize the evidence behind current recommendations for antithrombotic therapy after bioprosthetic AVR, identify evidence gaps, and present the design a randomized trial that aims to address some of these evidence gaps. Chapter 1 introduces each included study with a brief summary. Chapter 2 is a narrative review summarizing guideline recommendation for antithrombotic therapy after bioprosthetic AVR and the evidence upon which they are based. Chapter 3 is an observational study describing antithrombotic prescribing practices in the VISION Cardiac Surgery cohort study. Chapter 4 is a systematic review and network meta-analysis of randomized studies of antithrombotic therapy after transcatheter aortic valve replacement. Chapter 5 is a systematic review and meta-analysis of randomized and observational studies of subclinical valve thrombosis. Chapter 6 presents the design and rationale of a feasibility trial of direct oral anticoagulants versus vitamin K antagonists in patients with a new surgical bioprosthetic AVR and atrial fibrillation. Chapter 7 discusses the implications, limitations, and future avenues of the research presented in this doctoral thesis. / Thesis / Doctor of Philosophy (PhD) / More than 10,000 Canadians require aortic valve replacement each year. Bioprosthetic valves (made out of cow or pig tissue) are often preferred over mechanical valves (made out of metal) because the risk of blood clots forming on the valve or causing a stroke is lower. The disadvantage of bioprosthetic valves is that they can wear out and require re-replacement. The reason why bioprosthetic valves wear out is uncertain, but it may be related to small blood clots on the valve that are only detectable on a CT scan. This doctoral thesis explores the use of blood thinners for patients with bioprosthetic aortic valve replacement. Ideally, blood thinners would be able to prevent blood clots and stroke, and to improve the durability of bioprosthetic valves, without causing too much bleeding. The thesis reviews the available evidence, identifies unanswered questions, and ends with a proposal for a study to generate new data.

Aortic Stenosis (AS) is the most common valvular heart disease. Aortic valve replacement (AVR) is the only acceptable treatment for AS. Several replacement methods are available to treat AS including conventional surgical aortic valve replacement (SAVR), transcatheter aortic valve replacement (TAVR), and Sutureless aortic valve replacement (SuAVR). SAVR showed excellent long-term results. However, it is an invasive procedure and is denied in substantial number of patients. TAVR showed excellent results and outcomes when compared to SAVR. However, it is associated with increased rate of paravalvular leaks that may impact long term outcomes. SuAVR has developed to overcome the drawbacks of SAVR and TAVR. SuAVR is associated with favorable short and midterm outcomes when compared to SAVR and TAVR. In this thesis, we summarize the safety, the evidence and the perceptions of using SuAVR in Canada. In Chapter1, we evaluated the use of SuAVR Perceval bioprosthesis in retrospective single center study of 415 patients with AS. SuAVR showed excellent immediate post-operative and hemodynamics outcomes. In chapter 2, we sought to establish perceptions and patterns to SuAVR use among Canadian cardiac surgeons. Sixty-Six Canadian cardiac Surgeons responded to the survey. Surgeons reported influential factors, barriers to use SuAVR, and their interest in a trial comparing SuAVR versus TAVR. Surgeons were likely to use SuAVR in high risk patients with hostile aortic root, small aortic annulus and in patients undergoing concomitant procedures whereas cost was the main limiting factor to use SuAVR in Canada. Majority of surgeons reported their interest in participating in a trial comparing SuAVR with TAVR. In chapter 3, we systematically reviewed and meta-analyzed the international evidence of using SuAVR versus SAVR and TAVR. SuAVR showed favorable or comparable results to SAVR and TAVR. However, long term and randomized data are needed to confirm these results. / Thesis / Master of Science (MSc) / Aortic valve stenosis (AS) is considered the most common valvular heart disease, which caused by narrowing of the aortic valve. Aortic valve replacement (AVR) is the only acceptable treatment to relieve the stenosis. Several strategies are available including conventional surgical aortic valve replacement (SAVR), transcatheter aortic valve replacement (TAVR), and sutureless aortic valve replacement (SuAVR). SAVR is an invasive procedure and denied in a considerable number of patients with aortic stenosis due to aging and presence of multiple diseases leading to higher risk of complications. TAVR is less invasive option and showed excellent results when compared to SAVR. However, it was associated with complications. SuAVR has developed to overcome some of the drawbacks of SAVR and TAVR. SuAVR is associated with short operation time and less complications compared to SAVR and TAVR. This thesis summarizes the safety, perceptions and evidence surrounding the use of SuAVR.

Symptomatic aortic stenosis (AS) is an increasing phenomenon as more adults live longer. The gold standard for treating AS is surgical aortic valve replacement (SAVR). Frequently, as older individuals with AS often have multiple comorbidities, a SAVR is determined to be too high risk. Therefore, a less invasive treatment option is available, namely a transcatheter aortic valve implantation (TAVI) or transcatheter aortic valve replacement (TAVR). Such biomedical procedures have encouraged life extension and the decision to intervene commonplace with the aging population. Without an intervention, significant debilitating symptoms affect a person's quality of life (QoL). Multiple quantitative studies evaluating QoL before and after a TAVI have been performed. However QoL has multiple attributes and is not a single construct. By limiting practice to these defined QoL measures, we exclude the human experience and what values individuals describe as important to them. The dilemma in the present medical model is influenced by two paradigms, evidence based medicine and patient centered medicine. Some people opt not to have a TAVI. This study aims to understand what it is like living with aortic stenosis as perceived by the participant and to gain a more meaningful understanding of why some individuals with AS choose not to have this procedure performed. Using a convenience sample of patients who declined a TAVI, a telephone interview with the person focused on their perceived QoL and the implications determining not to pursue a TAVI. In this qualitative phenomenological design, open-ended questions included: 1) What is it like to live with Aortic Stenosis. 2) Why did you choose not to have the TAVI? Interviews will explore emerging themes. Advanced practice nurses are in ideal positions for performing research to gain greater insight on the complexity of people's health choices. As the incidence of AS occurs more frequently in the increasing aged population, TAVI offers a treatment option for those patients who are symptomatic with AS and are not surgical candidates. However, health care providers should focus on the illness, not the disease, and explore the patients' biopsychosocial values with their medical needs. The information gathered in this study will help guide heath care providers with offering holistic health care incorporating both paradigms of evidence based practice and patient centered medicine options on treatment for people with symptomatic AS.

BACKGROUND: Calcific aortic valve disease (CAVD) is the most prevalent heart valve disease in the developed world, claiming almost 17,000 deaths annually in the United States. The lack of noninvasive therapeutics to slow or halt the disease warrants the need for further understanding of the pathobiological mechanisms of CAVD. A tri-laminar structure of aortic valve determines the biomechanical properties of its leaflets. Valvular endothelial cells (VECs) and interstitial cells (VICs) are responsible for valve structural integrity. Traditional two-dimensional culture conditions spontaneously activate the pathological differentiation of VICs making in vitro studies challenging. A monolayered three-dimensional (3D) hydrogel platform was recently developed as a novel in vitro culture system to study the phenotypic changes of VICs leading to microcalcification (early stages of calcification). This system, however, did not fully recapitulate the microenvironment of native valve tissues because of the lack of individual layer representations and endothelial coverage. Bioprinting technology, which allows precise and integrated positioning of cells, matrix, and biomolecules, may provide an innovative approach toward building a more biologically relevant 3D culture platform. OBJECTIVE: This study aims to lay the groundwork for building a multilayered 3D-bioprinted culture platform to study CAVD by first validating the use of bioprinting in monolayered cell-laden 3D hydrogel constructs. METHODS: Human VICs were isolated from patients undergoing valve replacement surgeries at Brigham and Women’s Hospital (Boston, MA) according to Institutional Review Board (IRB) protocols. VICs were expanded in culture medium containing growth factors for up to 6 passages and then encapsulated in hydrogels using 3D bioprinting technology. After encapsulation, VIC-laden 3D constructs were cultured in either normal or osteogenic conditions for 21 days. Microcalcification, cell proliferation, and cell apoptosis were evaluated using fluorescent staining and confocal microscopy. Results were compared with results from VIC-laden hydrogels made manually. RESULTS: An increase in microcalcification was observed throughout bioprinted VIC-laden hydrogel constructs cultured in osteogenic conditions for 21 days, whereas normal conditions developed negligible calcification signals. Cell proliferation and apoptosis were not significantly different between normal and osteogenic groups in bioprinted hydrogels. Cell-free hydrogels did not exhibit any microcalcification. Overall, bioprinted hydrogels showed less nonspecific background staining than handmade hydrogels, thus providing a better means for quantitative assessments of 3D culture platforms. CONCLUSION: Based on bioprinting technology, an improved monolayered cell-laden hydrogel platform was successfully established as a first step toward building an in vitro multilayered disease model for studying the pathobiological mechanisms of CAVD. The results in this study were consistent with current literature that proposes calcification as a cell-dependent, apoptotic-independent, and proliferation-independent pathway. / 2019-07-13T00:00:00Z

Le rétrécissement aortique calcifié dégénératif (RAC) représente la principale pathologie valvulaire cardiaque dans les pays occidentaux (2% à 7% de la population après 65 ans). Il n’existe, à ce jour, aucun traitement médical qui permette de stopper ou de prévenir la progression du RAC. Le seul traitement du RAC sévère est le remplacement valvulaire aortique chirurgical ou par cathétérisme (TAVI) en cas de symptômes (dyspnée,douleur thoracique ou syncope), de dysfonction ventriculaire gauche (FEVG<50%) ou de mauvaise tolérance fonctionnelle lors d’un test d’effort. À l’inverse, la prise en charge des patients asymptomatiques avec un RAC sévère est controversée devant le risque de mort subite ou de détérioration myocardique irréversible sans traitement et le risque de la chirurgie cardiaque prophylactique et des complications prothétiques. De plus, le RAC intéresse une population de plus en plus âgée où la présence de symptômes peut être difficilement évaluable et où s’associent des facteurs de risques et des comorbidités cardiovasculaires rendant la stratégie clinique de plus en plus compliquée. Enfin, il semble que parmi les patients avec un RAC serré asymptomatique, certains sont à plus haut risque d’évènements et bénéficieraient peut être d’une chirurgie plus précoce. L’identification de marqueurs de progression et pronostiques objectifs dans ce sous-groupe de patients constitue donc un enjeu très important. / Aortic valve stenosis (AS) is the most common valvular heart disease in Westerncountries AS (2%–7% of the population after 65 years old) for which valve replacement is theonly curative treatment. Current guidelines recommend surgery in patients with severe ASand either symptoms or left ventricular systolic dysfunction (LVEF<50%). However,treatment of asymptomatic patients remains controversial due, on the one side, to the riskof sudden death without preceding symptoms and irreversible myocardial dysfunction and,on the other side, to the risk of surgery and prosthetic valve complications. Identifyingsubsets of asymptomatic AS patients with preserved left ventricular ejection fraction whomay benefit from early or prophylactic surgery is therefore a critical clinical challenge.

Aortic valve disease is among the third most common cardiovascular disease worldwide, and is also a strong predictor for other cardiac related deaths. Altered mechanical forces are believed to cause changes in aortic valve biosynthetic activity, eventually leading to valve disease, however little is known about the cellular and molecular events involved in these processes. To gain a fundamental understanding into aortic valve disease mechanobiology, an ex vivo experimental model was used to study the effects of normal and elevated cyclic stretch on aortic valve remodeling and degenerative disease. The hypothesis of this proposal was that elevated cyclic stretch will result in increased expression of markers related to degenerative valve disease. Three aspects of aortic valve disease were studied: (i) Altered extracellular matrix remodeling; (ii) Aortic Valve Calcification; and (iii) Serotonin-induced valvulopathy. Results showed that elevated stretch resulted in increased matrix remodeling and calcification via a bone morphogenic protein-dependent pathway. In addition, elevated stretch and serotonin resulted in increased collagen biosynthesis and tissue stiffness via a serotonin-2A receptor-mediated pathway. This work adds to current knowledge on aortic valve disease mechanisms, and could pave the way for the development of novel treatments for valve disease and for the design of tissue engineered valve constructs.

Diss. Linköping : Linköpings universitet, 2008.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 5 uppsatser.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13399号 / 論医博第2223号 / 新制||医||1051(附属図書館) / (主査)教授 今中 雄一, 教授 佐藤 俊哉, 教授 福田 和彦 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM