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.

Role of Hemodynamic Shear Stress Abnormalities in the Early Pathogenesis of Bicuspid Aortic Valve Calcification

2013 ◽  
Author(s):  
Ling Sun ◽  
Santanu Chandra ◽  
Philippe Sucosky
Keyword(s):  
Shear Stress ◽  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
The United States ◽  
Cardiac Anomaly ◽  
Type I ◽  
Calcific Aortic Valve Disease ◽  
Congenital Cardiac Anomaly ◽  
Valvular Calcification ◽  
Right Coronary Cusp

With a prevalence of 1.3 million cases in the United States, the bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly and is frequently associated with calcific aortic valve disease (CAVD) [1]. The most prevalent type-I morphology, which results from left-/right-coronary cusp fusion, generates different hemodynamics than a tricuspid aortic valve (TAV). While valvular calcification has been linked to genetic and atherogenic predispositions, hemodynamic abnormalities are increasingly pointed as potential pathogenic contributors [2–3]. In particular, the wall shear stress (WSS) produced by blood flow on the leaflets regulates homeostasis in the TAV. In contrast, WSS alterations cause valve dysfunction and disease [4]. While such observations support the existence of synergies between valvular hemodynamics and biology, the role played by BAV WSS in valvular calcification remains unknown. The objective of this study was to isolate the acute effects of native BAV WSS abnormalities on CAVD pathogenesis.

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.

scholarly journals Proteo-transcriptomic analysis of osteogenic differentiation of valve interstitial cells from patients with calcific aortic valve disease

Bone Reports ◽  
2020 ◽  
Vol 13 ◽  
pp. 100303
Author(s):  
Arseniy Lobov ◽  
Daria Semenova ◽  
Aleksandra Kostina ◽  
Artem Kiselev ◽  
Arsenii Zabirnyk ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Osteogenic Differentiation ◽  
Aortic Valve Disease ◽  
Interstitial Cells ◽  
Transcriptomic Analysis ◽  
Valve Disease ◽  
Calcific Aortic Valve Disease ◽  
Valve Interstitial Cells

scholarly journals Label-free optical biomarkers detect early calcific aortic valve disease in a wild-type mouse model

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ishita Tandon ◽  
Shelby Johns ◽  
Alan Woessner ◽  
Jessica Perez ◽  
Delaney Cross ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Early Detection ◽  
Mouse Model ◽  
Osteogenic Differentiation ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
Label Free ◽  
Calcific Aortic Valve Disease ◽  
Collagen Remodeling ◽  
Positive Expression

Abstract Background Calcific aortic valve disease (CAVD) pathophysiology is a complex, multistage process, usually diagnosed at advanced stages after significant anatomical and hemodynamic changes in the valve. Early detection of disease progression is thus pivotal in the development of prevention and mitigation strategies. In this study, we developed a diet-based, non-genetically modified mouse model for early CAVD progression, and explored the utility of two-photon excited fluorescence (TPEF) microscopy for early detection of CAVD progression. TPEF imaging provides label-free, non-invasive, quantitative metrics with the potential to correlate with multiple stages of CAVD pathophysiology including calcium deposition, collagen remodeling and osteogenic differentiation. Methods Twenty-week old C57BL/6J mice were fed either a control or pro-calcific diet for 16 weeks and monitored via echocardiography, histology, immunohistochemistry, and quantitative polarized light imaging. Additionally, TPEF imaging was used to quantify tissue autofluorescence (A) at 755 nm, 810 nm and 860 nm excitation, to calculate TPEF 755–860 ratio (A860/525/(A755/460 + A860/525)) and TPEF Collagen-Calcium ratio (A810/525/(A810/460 + A810/525)) in the murine valves. In a separate experiment, animals were fed the above diets till 28 weeks to assess for later-stage calcification. Results Pro-calcific mice showed evidence of lipid deposition at 4 weeks and calcification at 16 weeks at the valve commissures. The valves of pro-calcific mice also showed positive expression for markers of osteogenic differentiation, myofibroblast activation, proliferation, inflammatory cytokines and collagen remodeling. Pro-calcific mice exhibited lower TPEF autofluorescence ratios, at locations coincident with calcification, that correlated with increased collagen disorganization and positive expression of osteogenic markers. Additionally, locations with lower TPEF autofluorescence ratios at 4 and 16 weeks exhibited increased calcification at later 28-week timepoints. Conclusions This study suggests the potential of TPEF autofluorescence metrics to serve as a label-free tool for early detection and monitoring of CAVD pathophysiology.

scholarly journals Bicuspid Aortic Valve Disease and Ascending Aortic Aneurysms: Gaps in Knowledge

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Katie L. Losenno ◽  
Robert L. Goodman ◽  
Michael W. A. Chu
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Valve Disease ◽  
Aortic Aneurysms ◽  
Valve Disease ◽  
Cardiac Anomaly ◽  
Aortic Dilatation ◽  
Congenital Cardiac Anomaly ◽  
Valvular Stenosis ◽  
Ongoing Surveillance

The bicuspid aortic valve is the most common congenital cardiac anomaly in developed nations. The abnormal bicuspid morphology of the aortic valve results in valvular dysfunction and subsequent hemodynamic derangements. However, the clinical presentation of bicuspid aortic valve disease remains quite heterogeneous with patients presenting from infancy to late adulthood with variable degrees of valvular stenosis and insufficiency and associated abnormalities including aortic coarctation, hypoplastic left heart structures, and ascending aortic dilatation. Emerging evidence suggests that the heterogeneous presentation of bicuspid aortic valve phenotypes may be a more complex matter related to congenital, genetic, and/or connective tissue abnormalities. Optimal management of patients with BAV disease and associated ascending aortic aneurysms often requires a thoughtful approach, carefully assessing various risk factors of the aortic valve and the aorta and discerning individual indications for ongoing surveillance, medical management, and operative intervention. We review current concepts of anatomic classification, pathophysiology, natural history, and clinical management of bicuspid aortic valve disease with associated ascending aortic aneurysms.

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.

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.

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