scholarly journals A Coupled Multiscale Approach to Modeling Aortic Valve Mechanics in Health and Disease

2021 ◽  
Vol 11 (18) ◽  
pp. 8332
Author(s):  
Ahmed A. Bakhaty ◽  
Sanjay Govindjee ◽  
Mohammad R. K. Mofrad
Keyword(s):  
Aortic Valve ◽  
Aortic Stenosis ◽  
Mechanical Behavior ◽  
Three Dimensional ◽  
Interstitial Cells ◽  
Multiscale Approach ◽  
Valvular Interstitial Cells ◽  
Calcific Aortic Stenosis ◽  
Multiple Length Scales ◽  
Health And Disease

Mechano-biological processes in the aortic valve span multiple length scales ranging from the molecular and cell to tissue and organ levels. The valvular interstitial cells residing within the valve cusps sense and actively respond to leaflet tissue deformations caused by the valve opening and closing during the cardiac cycle. Abnormalities in these biomechanical processes are believed to impact the matrix-maintenance function of the valvular interstitial cells, thereby initiating valvular disease processes such as calcific aortic stenosis. Understanding the mechanical behavior of valvular interstitial cells in maintaining tissue homeostasis in response to leaflet tissue deformation is therefore key to understanding the function of the aortic valve in health and disease. In this study, we applied a multiscale computational homogenization technique (also known as “FE2”) to aortic valve leaflet tissue to study the three-dimensional mechanical behavior of the valvular interstitial cells in response to organ-scale mechanical loading. We further considered calcific aortic stenosis with the aim of understanding the likely relationship between the valvular interstitial cell deformations and calcification. We find that the presence of calcified nodules leads to an increased strain profile that drives further growth of calcification.

scholarly journals Molecular aspects of the pathological activation and differentiation of valvular interstitial cells during the development of calcific aortic stenosis

2019 ◽  
Vol 34 (3) ◽  
pp. 66-72
Author(s):  
A. E. Kostyunin
Keyword(s):  
Aortic Stenosis ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Interstitial Cells ◽  
Valvular Interstitial Cells ◽  
Calcific Aortic Stenosis ◽  
Valve Tissue ◽  
Pathological Differentiation ◽  
Molecular Aspects ◽  
Atherosclerotic Process

Calcific aortic stenosis is the most common valvular heart disease. The pathogenesis of this disease is complex and resembles the atherosclerotic process in the blood vessels. It is known that valvular interstitial cell activation and subsequent differentiation into osteoblast- and myofibroblast-like cells is the main driving force of fibrous and calcified aortic valve tissue. However, the molecular mechanisms behind these processes are still not fully understood. Current information on this issue is collected and analyzed in this article. The main molecular pathways mediating the pathological differentiation of the valvular interstitial cells and the reasons for their activation are considered.

Multiscale Fluid-Structure Simulations of the Aortic Valve

2007 ◽  
Author(s):  
Eli Weinberg ◽  
Mohammad Mofrad
Keyword(s):  
Endothelial Cells ◽  
Aortic Valve ◽  
Three Dimensional ◽  
Interstitial Cells ◽  
Mechanical State ◽  
Valvular Interstitial Cells ◽  
Length Scales ◽  
Surrounding Environment ◽  
Cell Tissue ◽  
Opening And Closing

In the heart aortic valve, maintenance of healthy conditions and transition to diseased conditions are modulated by the cells in the valve. The cells found within the valve leaflets and walls are the valvular interstitial cells (VICs), and those found on the fluid-facing surfaces are the endothelial cells (ECs). Both types of cell are known to respond to their mechanical state; that is, the stresses and deformations imposed on the cell by its surrounding environment. Here, we present a set of simulations to examine the mechanical states of cells as the valve goes through its opening and closing cycle. The simulations span the cell, tissue, and organ length scales. Taken together, these simulations predict the dynamic, three-dimensional mechanical state of VICs and ECs throughout the valve.

P4485The number of lipoprotein(a) kringle IV-type 2 repeats is associated with the osteogenic profile of aortic valvular interstitial cells induced by plasma from patients with calcific aortic stenosis

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D A Arangalage ◽  
T S Simon ◽  
M V Varret ◽  
M C Croyal ◽  
B A Arsenault ◽  
...  
Keyword(s):  
Aortic Stenosis ◽  
Interstitial Cells ◽  
Calcium Deposition ◽  
Valvular Interstitial Cells ◽  
Pathogenic Role ◽  
Alizarin Red ◽  
Calcific Aortic Stenosis ◽  
Lipoprotein A ◽  
Osteoblastic Phenotype

Abstract Background Considerable progresses have been made in the invasive treatment of calcific aortic stenosis (AS), but there is still no pharmacological treatment available because the exact mechanism leading to the initiation of valvular calcification remains unknown. An increasing number of evidences, including large-scale genetic studies, have linked Lipoprotein(a) (Lp(a)) to AS but its pathogenic role in the osteoblastic transition of valvular interstitial cells (VIC) has remained undeciphered. Objective We sought to study the mechanistic link between the transition of VICs towards an osteoblastic phenotype leading to intraleaflet calcium deposition and the type of Lp(a) isoform, defined by the number of kringle IV-type 2 (KIV 2) repeats, in the plasma of patients with AS compared with healthy controls. Methods VICs isolated from healthy aortic valves were cultured in the presence of plasma samples deriving from 100 patients with severe AS included in the prospective cohort GENERAC and 50 matched control patients exempt from any aortic valve disease. We evaluated the number of Lp(a) KIV 2 repeats of each plasma preparation by liquid chromatography-mass spectrometry. The phenotypic changes of VICs towards an osteoblastic phenotype were assessed by immunofluorescence microscopy (osteocalcin expression) and Alizarin red staining (calcium deposition). Results Incubation of VICs with the plasma of AS patients triggered their transformation towards an osteoblastic phenotype, evidenced by the production of osteocalcin, and calcium deposition. There was no association between the plasma levels of Lp(a) and the extent of calcium deposition in the study population. However, a negative and significant correlation was found between calcium deposition and the number of KIV-2 repeats in the Lp(a) of the different plasma preparations (r=−0.20, p=0.038). A direct, causal role of Lp(a) isoforms containing a low number of KIV-2 repeats (5 to 6) in the transition of VICs towards an osteoblastic phenotype was supported by experiments performed with preparations of these isoforms, isolated from the plasma of blood donors. Conclusion A low number of KIV–2 repeats in plasma Lp(a) triggers the acquisition of an osteoblastic phenotype by VICs. The isoform, rather than the concentration of Lp(a) may play a pathogenic role in AS. Determining the number of KIV-2 repeats in the Lp(a) of patients may allow to identify subgroups of patients with an increased risk of developing AS. Acknowledgement/Funding ANR-16-RHUS-0003_STOP-AS. PHRC National 2005 and 2010, and PHRC regional 2007.

scholarly journals Upregulated Autophagy in Calcific Aortic Valve Stenosis Confers Protection of Valvular Interstitial Cells

2019 ◽  
Vol 20 (6) ◽  
pp. 1486 ◽  
Author(s):  
Miguel Carracedo ◽  
Oscar Persson ◽  
Peter Saliba-Gustafsson ◽  
Gonzalo Artiach ◽  
Ewa Ehrenborg ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Stenosis ◽  
Interstitial Cells ◽  
Left Ventricular ◽  
Autophagic Flux ◽  
Valvular Interstitial Cells ◽  
Survival Mechanism ◽  
Calcified Tissue ◽  
Left Ventricular Outflow

Autophagy serves as a cell survival mechanism which becomes dysregulated under pathological conditions and aging. Aortic valve thickening and calcification causing left ventricular outflow obstruction is known as calcific aortic valve stenosis (CAVS). CAVS is a chronic and progressive disease which increases in incidence and severity with age. Currently, no medical treatment exists for CAVS, and the role of autophagy in the disease remains largely unexplored. To further understand the role of autophagy in the progression of CAVS, we analyzed expression of key autophagy genes in healthy, thickened, and calcified valve tissue from 55 patients, and compared them with nine patients without significant CAVS, undergoing surgery for aortic regurgitation (AR). This revealed a upregulation in autophagy exclusively in the calcified tissue of CAVS patients. This difference in autophagy between CAVS and AR was explored by LC3 lipidation in valvular interstitial cells (VICs), revealing an upregulation in autophagic flux in CAVS patients. Inhibition of autophagy by bafilomycin-A1 led to a decrease in VIC survival. Finally, treatment of VICs with high phosphate led to an increase in autophagic activity. In conclusion, our data suggests that autophagy is upregulated in the calcified tissue of CAVS, serving as a compensatory and pro-survival mechanism.

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