The optimal timing of valve replacement surgery in chronic severe aortic regurgitation (AR) has remained a major clinical problem in the management of these patients. Although the onset of symptoms is the generally accepted indication for aortic valve replacement (AVR), the unpredictable development of pre-symptomatic left ventricular (LV) dysfunction as a result of prolonged volume overload has resulted in numerous reports attempting to formulate a risk profile for these patients. Although aortic root and LV cineangiography have been the "gold standard" for defining the severity of AR and its effect on LV performance, serial follow-up by these means is impractical. More recently numerous non-invasive measures of LV size (echocardiogram) and function both at rest and on exercise (echocardiogram and equilibrium radionuclide angiocardiography., ERNA) have been serially utilised~ In these endeavours, the thinking has been clouded by a tendency to equate these two measures and failing to appreciate that apparent preoperative LV dysfunction (particularly on exercise) may be rapidly reversible by AVR and the consequent changes in LV loading conditions. This study was a prospective, sequential evaluation of left ventricular function using both non-invasive and invasive techniques in symptomatic and asymptomatic patients with isolated chronic, severe (4+) AR at cardiac catheterisation. The aims of the study were to (I) Identify differences in the clinical, echocardiographic, resting and exercise haemodynamic and I radionuclide measures of left ventricular function in symptomatic and asymptomatic patients with chronic severe A.R. with particular reference to the incidence of presymptomatic development of left ventricular dysfunction. (II) Critically evaluate the role of exercise stress (both isotonic and isometric) in the assessment of patients with chronic severe A.R. (III) Evaluate the influence of time (sequential studies) on the haemodynamic burden in asymptomatic patients. (IV) Study the impact of successful aortic valve replacement on the reversibility of abnormal pre-operative LV function in an attempt to predict which patients would benefit from this therapeutic intervention and whether operation for symptoms alone is the correct clinical practice.

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.

Aortic valve (AV) disease is a major cause of cardiovascular-linked deaths globally. In addition, AV disease is a strong risk factor for additional cardiovascular events; however, the mechanism by which it initiates and progresses is not well-understood. We hypothesize that low and oscillatory flow is present on the fibrosa side of the AV and stimulates ECs to differentially regulate microRNA (miRNA) and mRNAs and influence AV disease progression. This hypothesis was tested employing both in vitro and in vivo approaches, high throughput microarray and pathway analyses, as well as a variety of functional assays. First, we isolated and characterized side-dependent, human aortic valvular endothelial cells (HAVECs). We found that HAVECs express both endothelial cell markers (VE-Cadherin, vWF, and PECAM) as well as smooth muscle cell markers (SMA and basic calponin). Using microarray analysis on sheared, side-specific HAVECs, we identified side- and shear-induced changes in miRNA and mRNA expression profiles. More specifically, we identified over 1000 shear-responsive mRNAs which showed robust validation (93% of those tested). We then used Ingenuity Pathway Analysis to identify key miRNAs, including those with many relationships to other genes (for example, thrombospondin and I&B) and those that are members of over-represented pathways and processes (for example, sulfur metabolism). Furthermore, we validated five shear-sensitive miRNAs: miR-139-3p, miR-148a, miR-187, miR-192, and miR-486-5p and one side-dependent miRNA, miR-370. To prioritize these miRNAs, we performed in silico analysis to group these key miRNAs by cellular functions related to AV disease (including tissue remodeling, inflammation, and calcification). Next, to compare our in vitro HAVEC results in vivo, we developed a method to isolate endothelial-enriched, side-dependent total RNA and identify and validate side-dependent (fibrosa vs. ventricularis) miRNAs in porcine aortic valvular endothelium. From this analysis, we discovered and validated eight side-dependent miRNAs in porcine endothelial-enriched AV RNA, including one miRNA previously identified in vitro, miR-486-5p. Lastly, we determined the relationship between important miRNAs (specifically miR-187 and miR-486-5p) and AV disease by modulating levels of miRNAs and performing functional assays. Preliminary studies overexpressing miR-187 in HAVECs have shown a reduction in inflammatory state through monocyte adhesion (p<0.05). Further, miR-486-5p overexpression reveals an increase in migration (p<0.05) and a trend for a decrease in early apoptosis, linking miR-486-5p to tissue remodeling in the AV. Better understanding of AV biology and disease in terms of gene-regulation under different hemodynamic conditions will facilitate the design of a tissue-engineered valve and provide alternative treatment options.