Abstract 295: Hemodynamic Shear Stress Alterations Contribute to Calcific Aortic Valve Disease in a Frequency- and Magnitude-Dependent Manner

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Ling Sun ◽  
John LeCluyse ◽  
Brian Robillard ◽  
Philippe Sucosky
Keyword(s):  
Shear Stress ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Ex Vivo ◽  
Fold Increase ◽  
Endothelial Activation ◽  
Valve Disease ◽  
Dependent Manner ◽  
Molecular Signaling ◽  
Calcific Aortic Valve Disease

INTRODUCTION: Calcific aortic valve disease (CAVD) is an active process presumably triggered by interplays between atherogenic risk factors, molecular signaling networks and hemodynamic cues. While our earlier work demonstrated that progressive alterations in fluid wall-shear stress (WSS) on the fibrosa could trigger leaflet inflammation, the mechanisms of CAVD pathogenesis secondary to side-specific WSS abnormalities are poorly understood. HYPOTHESIS: Supported by our previous studies, we hypothesize that valve leaflets are sensitive to both WSS magnitude and pulsatility and that abnormalities in either promote CAVD development. OBJECTIVE: This study aims at elucidating ex vivo the contribution of isolated and combined alterations in WSS magnitude and pulsatility to valvular calcification. METHODS: The fibrosa and ventricularis of porcine leaflets were subjected simultaneously to different combinations of WSS magnitude and pulsatility (i.e., physiologic, sub- and supra-physiologic levels) for 48 hours in a double-sided shear stress bioreactor. Endothelial activation (ICAM-1, VCAM-1), paracrine expression (TGF-β and BMP-4), and proteinase/collagenase expression (MMP-2, cathepsin L) were detected by immunohistochemistry, while osteogenic differentiation (α-SMA) was assessed via western blot. RESULTS: Regardless of the magnitude or frequency, non-physiologic WSS conditions did not result in endothelial activation. Tissue exposure to either supra-physiologic WSS magnitude or pulsatility significantly upregulated paracrine (74-fold increase), proteinase (4-fold increase), collagenase (5-fold increase) and α-SMA (23-fold increase) expressions relative to the levels measured under physiologic WSS. In contrast, combined alterations in WSS magnitude and pulsatility downregulated those responses. CONCLUSION: This study demonstrates the sensitivity of aortic valve leaflets to both WSS magnitude and pulsatility and the ability of supra-physiologic WSS magnitude or pulsatility to trigger events involved in early CAVD pathogenesis. The results provide new potential insights into the mechanisms of CAVD secondary to hypertension and Paget’s disease, which are associated with abnormal blood flow and leaflet WSS.

Contribution of Hemodynamic Shear Stress Magnitude and Frequency Abnormalities to Calcific Aortic Valve Disease Pathogenesis

2013 ◽  
Author(s):  
Ling Sun ◽  
Philippe Sucosky
Keyword(s):  
Shear Stress ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Fluid Shear Stress ◽  
Ex Vivo ◽  
Valve Disease ◽  
Molecular Signaling ◽  
Fluid Shear ◽  
Calcific Aortic Valve Disease ◽  
Hemodynamic Shear Stress

Calcific aortic valve disease (CAVD) is an active process presumably triggered by interplays between atherogenic risk factors, molecular signaling networks and hemodynamic cues. While our earlier work demonstrated that progressive alterations in fluid shear stress (FSS) on the fibrosa could trigger valvular inflammation [1], the mechanisms of CAVD pathogenesis secondary to side-specific FSS abnormalities are poorly understood. Supported by our previous studies, we hypothesize that valve leaflets are sensitive to both WSS magnitude and pulsatility and that abnormalities in either promote CAVD development. This study aims at elucidating ex vivo the contribution of isolated and combined alterations in FSS magnitude and pulsatility to valvular calcification.

Abstract 141: Bicuspid Aortic Valve Hemodynamic Abnormalities Promote Early Development of Calcific Aortic Valve Disease

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Ling Sun ◽  
Santanu Chandra ◽  
Philippe Sucosky
Keyword(s):  
Shear Stress ◽  
Aortic Valve ◽  
Osteogenic Differentiation ◽  
Bicuspid Aortic Valve ◽  
Aortic Valve Disease ◽  
Tissue Response ◽  
Valve Disease ◽  
Type I ◽  
Calcific Aortic Valve Disease ◽  
Congenital Cardiac Anomaly

INTRODUCTION: The bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly and is frequently associated with calcific aortic valve disease (CAVD). Although CAVD also develops in the normal tricuspid aortic valve (TAV), its progression in the BAV is more rapid. While the accelerated calcification of BAV leaflets has been linked to genetic and atherogenic predispositions, hemodynamic abnormalities are increasingly pointed as potential pathogenic contributors. HYPOTHESIS: Supported by our previous work, which demonstrated the sensitivity of valve leaflets to the surrounding blood flow and associated wall-shear stress (WSS), we hypothesize that the abnormal WSS experienced by BAV leaflets contribute to CAVD development by promoting valvular inflammation, remodeling and osteogenic differentiation. OBJECTIVE: This study aims at comparing ex vivo the effects of TAV and BAV leaflet WSS on valvular pathogenesis. METHODS: The native, side-specific WSS experienced by TAV and type-I (i.e., fused and non-coronary) BAV leaflets were obtained computationally using fluid-structure interaction simulations. Fresh porcine leaflets were subjected for 48 hours to each of the three WSS conditions using a novel double-sided shear stress bioreactor. Tissue response was characterized via Western blot and immunohistochemistry in terms of markers of endothelial activation (VCAM-1, ICAM-1), paracrine expression (BMP-4), TGF-β/Wnt signaling pathways (TGF-β1, β-catenin), extracellular matrix remodeling (cathepsin L, MMP-2, MMP-9) and osteogenic differentiation (α-SMA, osteocalcin). RESULTS: No significant differences in VCAM-1 and ICAM-1 expressions were detected between tissue exposed to TAV and BAV WSS. While the native WSS experienced by the TAV and non-coronary BAV leaflets maintained tissue homeostasis, tissue exposure to the fused BAV leaflet WSS resulted in a significant pathological response marked by the upregulations of BMP-4, β-catenin, MMP-2 and osteocalcin expressions. CONCLUSION: This study demonstrates the pathological nature of the native BAV hemodynamics and confirms the higher susceptibility of the fused BAV leaflet to calcify. The results provide new insights into the hemodynamic theory of BAV calcification.

scholarly journals Decreased Glucagon-Like Peptide-1 Is Associated With Calcific Aortic Valve Disease: GLP-1 Suppresses the Calcification of Aortic Valve Interstitial Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Fan Xiao ◽  
Qing Zha ◽  
Qianru Zhang ◽  
Qihong Wu ◽  
Zhongli Chen ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Interstitial Cells ◽  
Valve Disease ◽  
Dependent Manner ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Objectives: This study explores the concentration and role of glucagon-like peptide-1 (GLP-1) in calcific aortic valve disease (CAVD).Background: Calcific aortic valve disease is a chronic disease presenting with aortic valve degeneration and mineralization. We hypothesized that the level of GLP-1 is associated with CAVD and that it participates in the calcification of aortic valve interstitial cells (AVICs).Methods: We compared the concentration of GLP-1 between 11 calcific and 12 normal aortic valve tissues by immunohistochemical (IHC) analysis. ELISA was used to measure GLP-1 in serum of the Control (n = 197) and CAVD groups (n = 200). The effect of GLP-1 on the calcification of AVICs and the regulation of calcific gene expression were also characterized.Results: The GLP-1 concentration in the calcific aortic valves was 39% less than that in the control non-calcified aortic valves. Its concentration in serum was 19.3% lower in CAVD patients. Multivariable regression analysis demonstrated that GLP-1 level was independently associated with CAVD risk. In vitro, GLP-1 antagonized AVIC calcification in a dose- and time-dependent manner and it down-regulated RUNX2, MSX2, BMP2, and BMP4 expression but up-regulated SOX9 expression.Conclusions: A reduction in GLP-1 was associated with CAVD, and GLP-1 participated in the mineralization of AVICs by regulating specific calcific genes. GLP-1 warrants consideration as a novel treatment target for CAVD.

Structural Deformation of Native Aortic Valve Leaflet Under Hypertension: An In Vitro Study

2009 ◽  
Author(s):  
C. H. Yap ◽  
H. S. Kim ◽  
L. P. Dasi ◽  
M. J. Weiler ◽  
K. Balachandran ◽  
...  
Keyword(s):  
Shear Stress ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Fluid Shear Stress ◽  
Complex Structure ◽  
Valve Disease ◽  
Structural Deformation ◽  
Fluid Shear ◽  
Calcific Aortic Valve Disease ◽  
Increased Risk

The aortic valve (AV) is a complex structure that functions in a complex dynamic environment. During systole, the valve leaflets bend at the base to open and experience fluid shear stress on both ventricular and aortic sides of the leaflet. During diastole, adverse pressure gradient closes the valve causing it to structurally support the systemic afterload pressure. Ex vivo experiments has shown that isolated mechanical forces such as pressure, membrane tension, and fluid shear stress affects the remodeling activities of the valve leaflets and also elicit pathological responses [1], potentially leading to calcific aortic valve disease in the long term. Clinically, patients with hypertension have increased risk of developing calcific aortic valve disease [2], which could be a result of the increased pressure or the increased stretch on the valve leaflets.

Abstract P332: Microfluidic Model Of Late-stage Calcific Aortic Valve Disease Develops Calcium Phosphate Mineralizations

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Melissa Mendoza ◽  
Mei-Hsiu Chen ◽  
Bruce Murray ◽  
Peter Huang ◽  
Gretchen Mahler
Keyword(s):  
Shear Stress ◽  
Calcium Phosphate ◽  
Aortic Valve ◽  
Late Stage ◽  
Aortic Valve Disease ◽  
Collagen I ◽  
Valve Disease ◽  
Calcium Deposition ◽  
Nodule Formation ◽  
Calcific Aortic Valve Disease

Introduction: Calcific aortic valve disease (CAVD) is an active pathological process leading to severe valve calcification. Late-stage CAVD is characterized by increased leaflet stiffness, disorganized collagen bundles and the deposition of glycosaminoglycans, such as chondroitin sulfate (CS), in the fibrosa layer. However, many details of the cellular pathological cascade remain unknown. Animal models such as mice, rabbits, and pigs are used in understanding human CAVD, but mice do not have similar anatomy, rabbits cannot spontaneously develop atherosclerotic lesions, and pigs require long, expensive and complex studies. Here we utilize microfluidic devices of the aortic valve fibrosa to model late-stage CAVD. Hypothesis: We assessed the hypothesis that microfluidic calcification will increase with increased shear rates and CS content. Methods: Valve-on-a-chip devices contained a hydrogel of 1.5 mg/mL collagen I-only healthy controls or 1.5 mg/mL collagen I with 1 mg/mL or 20 mg/mL CS. Porcine aortic valve interstitial cells (PAVIC) were embedded within and endothelial cells (PAVEC) were seeded onto the matrix. Steady shear stress at 1 dyne/cm 2 and 20 dyne/cm 2 were applied using a peristaltic pump for 14 days. Alizarin Red S (ARS), an assay to assess calcium deposition, was used to quantify calcific nodule formation. Scanning electron microscopy with energy dispersive x-ray (SEM/EDX) was used to further analyze sample mineralization. Results: Co-cultures in the presence of increasing shear stress and CS exhibit increased calcific nodule formation compared to static controls, both qualitatively and quantitatively (n≥3). SEM revealed the microstructure of calcified nodules and EDX confirmed calcium phosphate mineralization with physiologically-relevant calcium to phosphorous ratios (Ca/P= 0.88 - 1.4). Conclusions: These results show that in vitro calcification is driven by shear stress in the presence of PAVEC and CS. As seen in ex vivo studies of human calcification, these microfluidic-derived nodules are similarly composed of a range of naturally-occurring calcium phosphates. Given that CAVD has no targeted therapy, the creation of a physiologically relevant model of the aortic valve can provide a test bed for novel therapeutic interventions.

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