5th Biennial Conference on Heart Valve Biology and Tissue Engineering

Transcatheter aortic valve replacement (TAVR) has revolutionized treatment for inoperable and high risk surgical patients with severe symptomatic aortic stenosis. Transcatheter aortic valves (TAVs) are deployed within the native diseased valve without sutures to secure them within the annulus. Oversizing of TAVs with respect to the annulus size is required to achieve appropriate anchoring. Optimal TAV function requires expansion of the frame to its nominal dimension. However, clinically TAVR results routinely in incomplete expansion of the stent frame. We have previously demonstrated that significant under-expansion results in suboptimal TAV function with impaired coaptation of TAV leaflets, but precise characteristics of TAV leaflets and frame after implantation have been poorly studied. The aim of this study was to determine the effect of TAV under-expansion as observed clinically on stress distribution and magnitude in the TAV stent and leaflets using finite element (FE) modeling. A computer aided design (CAD) model of a TAV was developed based on the 23mm Edwards-SAPIEN design and used to create a finite element (FE) model. The 3D model consists of a stent, three pericardial leaflets, a clamp compression unit and an expandable balloon. Large deformation FE simulations were conducted to model the TAVR procedure, including TAV crimping followed by balloon-expansion to 17, 21, and 23mm. Stress distribution on the stent and leaflets were determined. As the post-inflation diameter increased, the von Mises stress on the TAV stent decreased. The maximum von Mises stresses of stent after expansion to 17, 21, and 23mm were 365, 346, and 262 MPa, respectively. However, unlike the stent, the leaflet stress increased as the post-inflation diameter increased. The peak von Mises stresses after expansion were 1.5, 1.3, and 2.4 MPa, respectively. We present the first FE simulation which was developed to model the TAVR procedure from crimping and balloon inflation of the TAV. Stress on stent and leaflets after implantation is dependent on the internal diameter of the inflated stent. While stress on the stent decreases with increasing TAV expansion, stress on the leaflets increases. FE modeling can be further applied evaluate whether a specific TAV size and design is optimal for a specific patient.

Sporadic mitral valve prolapse (MVP) is a common valvular disorder affecting 2-3% of the humans worldwide. Unlike MVP in Marfan’s and Ehlers-Danlos syndromes, no specific genetic mutations that impact tissue homeostasis are currently identified. Yet, significant degenerative leaflet changes are observed, manifesting as leaflet weakening and billowing. In this study, we hypothesized that assessing the matrix health by investigating the activity of matrix synthetic and degradative markers would provide insights into the leaflet degeneration processes. Mitral leaflets were obtained from eight humans (N =8) undergoing surgical repair for MVP at our institution. Fresh leaflets were rinsed, stored in sterile PBS and divided into annulus, base or edge regions and used for immunohistochemistry(IHC) and western blotting(WB). Matrix synthetic activity was assessed using assays for: prolyl-4-hydroxylase(P4H–collagen synthesis enzyme), heat shock protein-47(HSP47–chaperone for collagen folding), and lysyl oxidase(LOX–collagen cross-linking). Matrix degradation was assessed using assays for matrix metalloproteases: MMP-1(collagen I degradation), MMP-3(collagen III degradation), and MMP-9(collagen V degradation). Tissue sections were imaged and quantitative analysis was performed using an image thresholding technique. Cell viability was confirmed using DAPI, and overall tissue structure assessed using H and E staining. Tissue section closest to the mitral annulus served as the control, against which the belly and edge expressions were compared. In the synthetic pathway, P4H activity decreased from 4±1.5 at the annulus to 2±1.3 at the belly (2X) and increased to 17±12 at the edge (4X). HSP47 activity was 3.2±2 in the annular section that increased to 5.1±2 in the belly (1.6X) and 4±1.3 in the edge (1.2X). LOX expression slightly increased from the annulus to the belly (1.2X), but was significantly higher in the edge (10X). In the degradative pathway, MMP-1 expression was 8.4±6.3 at the annulus, which decreased to 5.6±2.8 in the belly (1.5X), and 6±2 in the edge (1.4X). MMP-3 expression significantly increased from the annulus to the edge, with 2.3±2 at the annulus, 7.7±5 at the belly (3.3X) and 24.5±10.6 at the edge (10.4X). MMP-9 expression decreased from the annulus (1.3±0.4) to the belly (0.7±0.2; 1.7X) and increased to 3±1 in the edge(2.4X). Collagen biosynthesis is adequate in the edge as evident from increased P4H activity, however nominal HSP47 activity indicates poor fibril maturation and folding, resulting in a weak matrix in spite of good cross linking from higher LOX expression. Increased MMP-3 and 9 activities in the edge signify degradation of collagen III and V, which may further weaken the matrix. Studies to investigate the regional differences in genetic, cellular and molecular pathways in MVP and the potential role of the elevated stress in leaflet degradation are necessary.

Recent echocardiographic studies described that almost 30% of patients with severe aortic valve stenosis on the basis of aortic valve area may paradoxically have a relatively low mean gradient despite a preserved left ventricular ejection fraction (EF). However the existence of this pathologic entity has been questioned mainly for the lack of invasive data. We aimed to describe the prevalence of patients with severely reduced aortic valve area and low gradient from a consecutive series of patients with aortic stenosis and normal EF undergoing cardiac catheterization. Sixty one consecutive patients with invasively measured aortic valve area < 0,6 cmq/mq (AHA/ACC definition for severe aortic stenosis) and EF> 50% formed the study population. Each patient underwent to right and left heart catheterization for a comprehensive invasive hemodynamic evaluation. Aortic valve area was measured by Gorlin formula. Cardiac output was measured by thermodilution or Fick method. Low mean gradient was defined < 30 mmHg. 16 % of patients were characterized by low GM despite severely reduced aortic valve area. Patients with low GM were characterized by significantly higher aortic valve area (0.47±0.09 vs 0.36±0.09 cm2/m2; p=0.0008) but similar left ventricular stroke volume (SV) (65±22 vs 65±17 ml; p=0.9) and cardiac output (4.8±1.1 vs 4.7±1.0; p=0.7). The prevalence of low flow (defined as SV < 35 ml/ m2) was similar between groups (50% vs 43%; p=0.3). There was no difference in term of age (78±10 vs 79±11 years; p=0.6), female gender (50% vs 48%; p=0.5), body surface area (1.79±0.4 vs 1.80±0.4; p=0.8), pulmonary artery systolic pressures (37±9 vs 35±11 mmHg; p=0.8), LV end diastolic pressure (16±4 vs 20±7; p=0.1) and mean wedge pressure (17±7 vs 15±7; p=0.2). Patients with low GM showed a higher mean AO pressure (111±14 vs 93±14; p=0.009) but similar level of aortic distensibility (0.78±0.3 vs 0.9±0.4 ml/mmHg; p=0.3). This invasive study confirms that a substantial percent of patients may have a low GM despite a severely reduced aortic valve area and normal EF. It should be acknowledge that the barely perception of this pathologic entity might have reduced the likelihood of patients to undergo catheterization leading to underestimation of the prevalence of this condition.