Objectives To compare incidence of aortic regurgitation (AR), paravalvular AR and valvular performance with Doppler hemodynamic parameters following transcatheter aortic valve replacement (TAVR) with Edwards valve (EV) versus CoreValve (CV). Currently, there are scarce data on post-TAVR echocardiographic outcomes comparing EV and CV. Methods PubMed and the Cochrane Center Register of Controlled Trials were searched through May 2015. Twenty studies (n = 11,244) comparing TAVR procedure that used EV (n = 6445) and CV (n = 4799) were included. End points were post-TAVR moderate to severe AR and paravalvular AR, effective orifice area (EOA), mean trans-aortic pressure gradient (MPG), peak trans-aortic pressure gradient (PPG) and left ventricular ejection fraction (LVEF). The mean difference (MD) or relative risk (RR) with 95% confidence interval (CI) was computed and p < 0.05 was considered as a level of significance. Results Moderate to severe AR and paravalvular AR were significantly lower in EV group (RR: 0.57, CI: 0.52–0.63, p < 0.00001 and RR: 0.40, CI: 0.25–0.63, p < 0.0001 respectively) compared to CV group. EOA and PPG were not significantly different between EV and CV groups. MPG was significantly lower among patients in CV group (MD: 1.08, CI: 0.05–2.10, p = 0.04). LVEF was significantly higher in patients in EV group (MD: 2.26, CI: 0.77–3.74, p = 0.03). Conclusions This study showed CV is associated with higher incidence of post-TAVR moderate to severe paravalvular AR. Echocardiographic valvular performance measures (MPG, LVEF) showed minimal but significant difference, which may not be clinically significant.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20231号 / 医博第4190号 / 新制||医||1019(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 湊谷 謙司, 教授 山下 潤, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21652号 / 医博第4458号 / 新制||医||1035(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川村 孝, 教授 福原 俊一, 教授 佐藤 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Hypertension, a risk factor for aortic valve stenosis, increases transvalvular load and can elicit extracellular matrix (ECM) remodeling. Elevated cyclic pressure and the vasoactive agent angiotensin II (Ang II) both promote collagen synthesis, an early hallmark of aortic sclerosis. It was hypothesized that increased collagen production induced by elevated pressure conditions or the presence of Ang II would affect the mechanical properties of leaflet tissue by decreasing extensibility. Porcine aortic valve leaflets were exposed to pressure conditions of increasing magnitude with and without Ang II. Biaxial mechanical testing was performed to determine peak stretch. Collagen content was determined using a quantitative dye-binding method. The results demonstrated Ang II and elevated pressure decrease the extensibility of leaflet tissue and increase the collagen content in the ECM. In conclusion, the results demonstrated that both elevated pressure and Ang II play a role in altering the biomechanical properties of aortic valve leaflets.

No description available.

<p> Various areas of studies on the natural and the prosthetic aortic valves are reviewed. </p> <p> A microtensile technique devised to investigate the inhomogeneous and anisotropic material properties of a porcine aortic valve's leaflets is described. Also, the theory and apparatus of a new stereophotogrammetric technique to define points in space by their Cartesian coordinates is introduced. The technique is used to investigate the local surface strains and curvatures of a porcine aortic valve's leaflets from 0 to 120 mm. Hg. in-vitro. </p> <p> It is found that the valve leaflets display marked inhomogeneity and anisotropy (orthotropy is assumed) in the elastic moduli and transition strains. For the non-coronary leaflet, the radial post-transition moduli vary from 42 to 215 gm/mm² with a mean of 111 gm/mm² (s.d. = 43 gm/mm²); and the radial transition strains vary from 30% to 70% with a mean of 58% (s.d. = 7%). Areas nearer the leaflet's coaptation edge tend to exhibit lower radial transition strains than the annulus edge. The central region of the leaflet is found to be the stiffest. For the same non-coronary leaflet, the circumferential post-transition moduli vary from 220 to 590 gm/mm² with a mean of 342 gm/mm² (s.d. = 118 gm/mm²); and the circumferential transition strains vary from 22% to 47% with a mean of 33% (s.d. = 3%). </p> <p> Inhomogeneity between leaflets is also observed; preliminary results seem to suggest that the non-coronary leaflet is the stiffest in the radial direction and the least stiff in the circumferential direction. In comparison, the right coronary leaflet exhibits the largest radial transition strains (~80% ) and the smallest circumferential transition strains (~25%). </p> <p> For the diastolic valve in-vitro, the circumferential strains are less than 10% at all pressures; therefore , this suggests pre-transition behaviour during diastole which is contrary to the general belief. Radial strains at diastole vary from 10% to well over 100% and show a definite tendency to increase from the sinus-annulus edge to the coaptation edge. The non-coronary leaflet is the least strained of the leaflets (10% to 60% at diastole). </p> <p> The determination of pre-or post-transition state at diastole is discussed and the implications of the results on stress analyses and trileaflet valve designs are noted. </p> / Thesis / Master of Engineering (ME)

No description available.

Calcific aortic valve disease (CAVD) occurs through multiple mutually non-exclusive mechanisms that are mediated by valvular interstitial cells (VICs). VICs undergo pathological differentiation during the progression of valve calcification; however the factors that regulate cellular differentiation are not well defined. Most commonly recognized are biochemical factors that induce pathological differentiation, but little is known regarding the biochemical factors that may suppress this process. Further, the contribution of matrix mechanics in valve pathology has been overlooked, despite increasing evidence of close relationships between changes in tissue mechanics, disease progression and the regulation of cellular response. In this thesis, the effect of matrix stiffness on the differentiation of and calcification by VICs in response to pro-calcific and anti-calcific biochemical factors was investigated. Matrix stiffness modulated the response of VICs to pro-calcific factors, leading to two distinct calcification processes. VICs cultured on the more compliant matrices underwent calcification via osteoblast differentiation, whereas those cultured on the stiffer matrices were prone to myofibroblast differentiation. The transition of fibroblastic VICs to myofibroblasts increased cellular contractility, which led to contraction-mediated, apoptosis-dependent calcification. In addition, C-type natriuretic peptide (CNP), a putative protective molecule against CAVD, was identified. CNP supressed myofibroblast and osteoblast differentiation of VICs, and thereby inhibited calcification in vitro. Matrix stiffness modulated the expression of CNP-regulated transcripts, with only a small number of CNP-regulated transcripts not being sensitive to matrix mechanics. These data demonstrate the combined effects of mechanical and biochemical cues in defining VIC phenotype and responses, with implications for the interpretation of in vitro models of VIC calcification and possibly disease devleopment. The findings from this thesis emphasize the necessity to consider both biochemical and mechanical factors in order to improve fundamental understanding of VIC biology.

In the United States alone, there are nearly 49,000 aortic valvular repairs or replacements each year, and this number is expected to rise. Unlike atherosclerosis, the molecular mechanisms contributing to this side-dependent disease development are limited, which contributes to the lack of therapeutic treatments. Once clinically manifested, options for treatment are limited to valvular replacement or repair. Therefore understanding the mechanobiology and cellular responses in aortic valves may provide important information for disease development and possible biomarkers or therapeutic treatments. Aortic valve disease occurs on one side of the valvular leaflet. The fibrosa side, which faces the aorta, is prone to disease development, while the ventricularis remains relatively unaffected. The hemodynamics is hypothesized to play a role in side dependent disease formation. The fibrosa endothelium is exposed to oscillatory flow while the ventricularis endothelium is exposed to a pulsatile unidirectional flow. Previous work by our group has shown that bone morphogenic protein-4 is a mechanosensitve inflammatory cytokine in the vasculature. In the following study, we proposed that mechanosensitive bone morphogenic proteins play a role in side specific aortic valve disease. Recently, the bone morphogenic proteins (BMPs) have been found in calcified human aortic valves. Furthermore, BMP-4 in vascular endothelial cells is increased by oscillatory shear stress. However, the role of the BMPs in aortic valve endothelial cells and their contribution to aortic valve calcification remains unstudied. Therefore, the overall objective of this dissertation was to investigate how disease and hemodynamics affects the BMP pathway and inflammation in human aortic valvular endothelial cells. By understanding how the bone morphogenic proteins are regulated and what roles they play in aortic valve disease, we will have better insight into endothelial cell regulation and contribution in aortic valve pathology. The central hypothesis of this project was that oscillatory flow conditions on the fibrosa side of the aortic valve stimulate endothelial cells to produce BMP-4, which then activates an inflammatory response leading to accumulation of inflammatory cells, calcification, and ultimately valve impairment. This hypothesis was tested through three specific aims using calcified human aortic valves, non-calcified human aortic valves, and side-specific human aortic valve endothelial cells. We first worked to establish the importance of the BMPs in the aortic valvular endothelium by looking at two populations of aortic valves: 1) calcified human aortic valves were obtained from patients undergoing valve replacement, and 2) non-calcified valves were obtained from recipient hearts of patients undergoing heart transplantation. Using immunohistochemical techniques, we examined the BMPs, BMP antagonists, and SMADs. Surprisingly, we identified that the ventricularis endothelium had higher BMP expression in both calcified and non-calcified human aortic valves. Furthermore, no disease-dependent BMP expression was detected. Next, we examined the BMP antagonists and found that there was robust BMP antagonist expression in the ventricularis endothelium and very low expression in the fibrosa endothelium. Finally, to determine if the BMP pathway was activated, we stained for the canonical BMP signaling molecule phosphorylated-SMAD 1/5/8 and found increased staining in the endothelium of calcified human aortic valves. Furthermore, a significant increase in SMAD 1/5/8 phosphorylation was seen in the endothelium of calcified fibrosa when compared to the non-calcified fibrosa. Finally, inhibitory SMAD 6 was significantly increased in the ventricularis endothelium of non-calcified human aortic valves. These findings suggest that preferential activation of BMP pathways, controlled by the balance between the BMPs and their inhibitors, play an important role in side-dependent calcification of human AVs. We next wanted to examine the role of shear stress in BMP regulation, but before doing so, we needed to examine the endothelial response to fluid shear stress to validate the phenotype of our isolated human aortic valve endothelial cells. KLF2 and eNOS expression in vascular endothelial cells has been shown to be increased by laminar flow and to have anti-inflammatory effects by decreasing VCAM-1 levels. Conversely, oscillatory shear stress has been shown to increase NF-kappa B translocation and increase ICAM-1 and E-selectin. We found laminar shear stress causes human aortic valve endothelial cells align parallel to flow and have robust increases of KLF2 and eNOS and decreases in VCAM-1 levels; however, laminar shear-treated cells had similar levels of NF-kappa B activation as oscillatory treated cells while ICAM-1 and E-selectin was not affected by shear stress. In contrast, oscillatory shear had higher levels of monocytes bound which may be due to eNOS's protective effects under laminar shear and robust VCAM-1 expression in oscillatory shear. These studies suggest differential regulation of human aortic valvular endothelial cells than published reports on human aortic endothelial cells which adds to the growing evidence that valvular endothelial cells are phenotypically different than vascular endothelial cells. After verifying the shear response of our endothelial cells, we next determined the shear response of the BMPs and BMP antagonists and described BMPs' effect on inflammation. Previously, BMP-4 has been shown in vitro and in vivo to be increased in endothelial cells exposed to oscillatory flow, while the closely-related BMP-2 has not been shown to be shear sensitive. In this study we have found that BMPs -2 and -4 are shear sensitive while BMP-6 is not. Furthermore, we have found that follistatin is decreased by laminar flow only in the ventricularis, while MGP1 is decreased in the fibrosa valvular endothelial cells under both oscillatory and laminar flow. Finally, incubation with noggin did not affect monocyte adhesion after shear, suggesting differential regulation of inflammation in human aortic valvular endothelial cells. By addressing the specific aims of this project, we have investigate disease- and side-dependent valvular endothelial BMP expression in vivo, shear regulation of valvular endothelial inflammation in vitro, and shear regulation of valvular endothelial BMP expression in vitro. Our results suggest that the BMP pathway is playing a role in side specific aortic valve disease development; however, regulation of the BMPs does not appear to be shear regulated in vivo. Other factors that may be affecting BMP production include including pulsatile pressures, bending stresses, cyclic stretch, and humeral stimuli present in the blood of the patients. However, in vitro we have found BMPs -2 and -4 to be shear-regulated in human aortic valvular endothelial cells. Shear-induced inflammation in human aortic valve endothelial cells seems to be VCAM-1-dependent, and BMP-independent. Finally, by identifying factors that are modulated in calcific- and shear-dependent processes, new targets for the early detection of aortic valve disease can be determined and new therapeutics to slow or stop the progression of aortic valve disease may be discovered.

Background: Aortic stenosis (AS) is the most common heart valve disease in Europe and North America. Age-related calcification of the valve is the commonest cause of acquired AS, especially in patients older than 70 years.Conventional surgical aortic valve replacement (SAVR) and the novel, minimally invasive transcatheter aortic valve implantation (TAVI), effectively preserve left ventricular (LV) function, relieve symptoms and improve survival in patients with severe symptomatic AS. However, patients with impaired LV function may carry significant operative risk, and long recovery time. In addition, such patients might have other comorbidities, and hence adding another challenge. Thus evaluation of ventricular function before and after AVR, as well as critical evaluation of TAVI patients should contribute to better clinical outcome. Methods: We studied LV function by conventional echocardiography before and after SAVR in the following groups; (I) 86 patients (aged 71±10 years) with severe AS and LV dysfunction; (II) 112 consecutive elderly AS patients (aged 77±2 years) and compared them with 72 younger patients (aged 60±1 years); (III)66 patients (age 70±2 years, 53 male) who underwent AVR for severe AS with concurrent LV dysfunction; (IV) 89 consecutive patients with symptomatic severeAS who underwent successful TAVI, 45 of whom received trans-apical TAVI (TA)(age 80.8±4.9 year, 26 male) and 44 trans-femoral TAVI (TF) (age 82.9±5.8 year,22 male).The conventional echocardiographic measurements were made according to the guidelines. Severe AS was identified by aortic valve mean pressure gradient &gt;40mmHg or valve area &lt;1.0 cm2. LV systolic dysfunction was identified as ejection fraction (EF) &lt;50%. LV long-axis function was presented by mitral annular plane systolic excursion ( MAPSE ) at lateral wall and septal wall, which were measured from apical four-chamber view. Also from the same view, LV septal and lateral wall deformation using STE as well as global longitudinal systolic strain. The LV systolic twist as the net difference between apical rotation and basal rotation was measured from the parasternal apical and basal short-axis views in the TAVI patients. Results: Study I: In the low flow and high gradient group, operative (30-day) mortality was 10%, and peri-operative mortality was associated with lower mean LVEF, higher mitral E:A ratio, peak systolic pulmonary artery pressure (PSPAP), and higher serum creatinine (all p&lt;0.001), NYHA class III–IV, concomitant coronary artery bypass graft (CABG), urgent surgery, and longer bypass-time (all p&lt; 0.05). Mortality at 4 years was 17%. Univariate predictors of 4-year mortality were: lower EF (p&lt;0.001), presence of restrictive LV filling (p&lt;0.001), raised PSPAP (p&lt;0.001) and CABG (p=0.037). However, only EF&lt;40 % (p=0.03), the presence of restrictive LV filling (p=0.033) and raised PSPAP (p&lt;0.01)independently predicted mortality in this group.Study II: Elderly patients had higher NYHA class, more frequent atrial fibrillation (AF), coronary artery disease (CAD), emergency operation and use of bioprosthetic valves. They also had shorter E-wave deceleration time (DT) and larger left atria (LA) (p&lt;0.05 for all). 30-day mortality was 12% vs 4 % (Log Rank x2=3.02, p=0.08) and long term mortality was 18% vs 7% (Log Rank x2=4.38,p=0.04) in the two groups, respectively. Age was not related to mortality after adjustment for other variables. Among all variables, anemia (OR 4.20, CI:1.02–6.86, p=0.04), cardiopulmonary bypass (CPB) time (OR 1.02, CI 1.01–1.04,p&lt;0.01), significant patient prosthesis mismatch (PPM) (OR 5.43, CI 1.04–18.40,p&lt;0.05) were associated with 30-day mortality in elderly patients. Their long-term mortality was related to CBP time (OR 1.02, CI 1.00–1.05, p=0.04),PPM (OR 4.64, CI 1.33–16.11, p=0.02) and raised LA pressure: DT (OR 0.94, CI0.84–0.99, p=0.03) and pulmonary artery systolic pressure (PASP) (OR 1.12, CI1.03–1.19, p&lt;0.001).STUDY III: Following SAVR peak aortic pressure gradient (AOPG) decreased and indexed valve area increased (64±3 to 19±1 mmHg and 0.30±0.01 to 0.89±0.03 cm2/m2, p&lt;0.001 for both). LVEF increased (from 45±1 to 54±2%;p&lt;0.001), LV end diastolic and end-systolic dimensions fell (LVEDD index: from 33±1 to 30±1 mm/m2; and LVESD index: from 27±1 to 20±1 mm/m2; (p&lt;0.01 forboth). LV diastolic dysfunction improved as evidenced by the fall in E/A ratio (from 2.6±0.2 to 1.9±0.4) and prolongation of total filling time; (from 29.2±0.6 to31.4±0.5 s/min, p=0.01 for both). Among all echocardiographic variables, LV dimensions (LVEDD index, OR 0.70, CI 0.52–0.97, p&lt;0.05; LVESD index, OR 0.57, CI 0.40–0.85, p=0.005) were the two independent predictors of post-operative LV functional recovery on multivariate analysis. A cut-off value ofpre-operative LVESD index&lt;=27.5 mm/m2 was 85% sensitive and 72% specific inpredicting intermediate-term recovery of LV function after AVR (AUC, 0.72, p=0.002). STUDY IV: Before TAVI, there was no difference between the two patient groups in gender, age, body surface area (BSA) and baseline LV function. However, left ventricular mass index (LVMi), left atrial volume index (LAVi) and tricuspid regurgitation pressure drop (TRPdrop) were increased in the TA group (p&lt;0.05).One week after TAVI, aortic pressure gradient (AOPG) markedly dropped in thetwo groups (both p&lt;0.001), LVEDD index and LVESD index fell but EF andmyocardial strain remained unchanged. Overall cavity twist reduced (p&lt;0.048).Significant LVESD index reduction was only seen in TF group (p=0.02) with a slight increase in LVEF (p=0.04). Lateral MAPSE increased only in the TF group(p=0.02). LV longitudinal systolic strain remained unchanged in TA patients while apical lateral strain increased in TF group. LV apical rotation fell in the two groups but basal rotation increased only in the TA patients (p=0.02). LAVi reduced in bothgroups and to a greater extent in TF TAVI (p=0.006), as did TRPdrop (p&lt;0.001). Conclusion: SAVR and TAVI are two effective treatments for severe AS patients.The severity of pre-operative systolic and diastolic LV dysfunction is the major predictor of mortality following SAVR for low-flow and high gradient AS.Peri-operative AVR survival is encouraging in the elderly. Long term mortality in the elderly is related to PPM, LV diastolic dysfunction and secondary pulmonary hypertension. LV functional recovery was evident in most patients with LV dysfunction after SAVR. A lower prevalence of LV functional recovery in patients with large pre-operative LVESD index might signify the loss of contractile reserveand thus predict post-operative functional recovery. TAVI results in significant early improvement of segmental and overall ventricular function, particularly in patients receiving the trans-femoral approach. The delayed recovery of the trans-apical TAVI group, we studied, might reflect worse pre-procedural diastolic cavity function.