scholarly journals Superimposed Tissue Formation in Human Aortic Valve Disease: Differences between Regurgitant and Stenotic Valves

2021 ◽  
Vol 8 (7) ◽  
pp. 79
Author(s):  
Boudewijn P. T. Kruithof ◽  
Aniek L. van Wijngaarden ◽  
Babak Mousavi Gourabi ◽  
Jesper Hjortnaes ◽  
Meindert Palmen ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Body Part ◽  
Free Edge ◽  
The Body ◽  
Valve Disease ◽  
Matrix Composition ◽  
Aortic Dilatation ◽  
Aortic Valves ◽  
Highly Active

The formation of superimposed tissue (SIT), a layer on top of the original valve leaflet, has been described in patients with mitral regurgitation as a major contributor to valve thickening and possibly as a result of increased mechanical stresses. However, little is known whether SIT formation also occurs in aortic valve disease. We therefore performed histological analyses to assess SIT formation in aortic valve leaflets (n = 31) from patients with aortic stenosis (n = 17) or aortic regurgitation due to aortic dilatation (n = 14). SIT was observed in both stenotic and regurgitant aortic valves, both on the ventricular and aortic sides, but with significant differences in distribution and composition. Regurgitant aortic valves showed more SIT formation in the free edge, leading to a thicker leaflet at that level, while stenotic aortic valves showed relatively more SIT formation on the aortic side of the body part of the leaflet. SIT appeared to be a highly active area, as determined by large populations of myofibroblasts, with varied extracellular matrix composition (higher collagen content in stenotic valves). Further, the identification of the SIT revealed the presence of foldings of the free edge in the diseased aortic valves. Insights into SIT regulation may further help in understanding the pathophysiology of aortic valve disease and potentially lead to the development of new therapeutic treatments.

scholarly journals Superimposed tissue formation in human aortic valve disease: differences between stenotic and regurgitant valves

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
B P T Kruithof ◽  
A L Van Wijngaarden ◽  
B Mousavi Gourabi ◽  
M Palmen ◽  
N Ajmone Marsan
Keyword(s):  
Aortic Valve ◽  
Aortic Stenosis ◽  
Aortic Regurgitation ◽  
Aortic Valve Disease ◽  
Smooth Muscle Actin ◽  
Body Part ◽  
Free Edge ◽  
Mechanical Stresses ◽  
The Body ◽  
Valve Disease

Abstract Introduction The formation of superimposed tissue (SIT), a layer on top of the original valve leaflet, has been described in patients with mitral regurgitation, as a major contributor of valve thickening and probably secondary to increased valve mechanical stress. However, little is known whether SIT formation also occurs in aortic valve disease. Both in the case of aortic stenosis or aortic regurgitation, the aortic valve (AV) is subjected to increased mechanical stresses, although different in type, extent and location. Purpose To characterize SIT formation in aortic stenosis and regurgitation. Methods Human diseased AV leaflets (n=31) were obtained from patients undergoing aortic valve replacement because of aortic stenosis (n=17) or aortic regurgitation (n=14). Histological analysis was performed and elastin staining was used to distinguish the SIT from the original leaflet. Alpha-smooth muscle actin (SMA) staining was performed to identify myofibroblasts and Masson's Trichrome staining to identify collagen fibres. Results In both regurgitant leaflets (RL) and stenotic leaflets (SL) SIT was found at both the ventricular and aortic side (94% of SL, 93% of RL) and could reach up to 50% of total leaflet thickness (Fig. A-C). Although the average SIT thickness did not differ between SL and RL (0.30 mm, standard error of the mean (SEM): ±0.04 for SL vs 0.38 mm, SEM: ±0.05 for RL; p=0.61), the distribution of SIT differed. The SIT at the free edge of the aortic valve was significantly thicker in the RL (0.39 mm, SEM: ±0.06 for SL vs 0.88 mm, SEM: ± 0.07 for RL; p<0.0001), whereas the SIT at the aortic side of the body part was thicker in the SL (0.099 mm, SEM: ±0.023 for SL vs 0.033 mm, SEM: ± 0.021 for RL; p<0.05). Although the SIT comprised of various compositions of extracellular matrix, the overall collagen content was higher in SIT of the SL (212 a.u., SEM: ±4.37 for SL vs 169 a.u., SEM: ±4.06 for RL; p<0.0001). Myofibroblasts were predominantly observed in the SIT as compared to the original leaflet in SL and RL (Fig. D,E; myofibroblast-positive area: 11.6%, SEM: ±3.1 for SIT vs 1.2%, SEM: ±0.3 for original leaflet; p<0.001). The density of myofibroblast in the SIT of the body part of the aortic leaflet, however, was higher in the SL (myofibroblast-positive area: 15.5%, SEM: ±2.0 for SL vs 4.1%, SEM: ±1.3 for RL; p<0.01), whereas the density of myofibroblast in the SIT of the free edge was higher in the RL (myofibroblast-positive area: 15.3%, SEM: ±3.7 for SL vs 4.0%, SEM: ±1.4 for RL; p<0.001). Conclusions Both in aortic stenosis and aortic regurgitation, the AV is characterized by SIT formation but with difference in distribution and composition. These observations suggest the involvement of hemodynamic and mechanical stresses in the regulation of SIT formation of the AV. Understanding the formation of SIT might provide new insights in pathology of AV disease. FUNDunding Acknowledgement Type of funding sources: None.

Platelet membrane-coated nanoparticles target sclerotic aortic valves in ApoE−/− mice by multiple binding mechanisms under pathological shear stress

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Yang ◽  
Y Song ◽  
Z Huang ◽  
J Qian ◽  
Z Pang ◽  
...  
Keyword(s):  
Shear Stress ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Binding Capacity ◽  
Platelet Membrane ◽  
Valve Disease ◽  
Funding Source ◽  
Aortic Valves ◽  
Coated Nanoparticles

Abstract Background Aortic valve disease is the most common valvular heart disease leading to valve replacement. The efficacy of pharmacological therapy for aortic valve disease is limited by the high mechanical stress at the aortic valves impairing the binding rate. We aimed to identify nanoparticle coating with entire platelet membranes to fully mimic their inherent multiple adhesion mechanisms and target the sclerotic aortic valve of apolipoprotein E-deficient (ApoE−/−) mice based on their multiple sites binding capacity under high shear stress. Methods Considering the potent interaction of platelet membrane glycoproteins with components present in sclerotic aortic valves, platelet membrane-coated nanoparticles (PNPs) were synthetized and the binding capacity under high shear stress was evaluated in vitro and in vivo. Results Compared with PNPs bound intensity in the static station, 161%, 59%, and 39% of attached PNPs remained adherent on VWF-, collagen-, and fibrin-coated surfaces under shear stress of 25dyn/cm2 respectively. PNPs demonstrated effectively adhering to von Willebrand factor, collagen and fibrin under shear stresses in vitro. In an aortic valve disease model established in ApoE−/− mice, PNPs group exhibited significant increase of accumulation in the aortic valves compared with PBS and control NP group. PNPs displayed high degrees of proximity or co-localization with vWF, collagen and fibrin, which exhibited good targeting to sclerotic aortic valves by mimicking platelet multiple adhesive mechanisms. Conclusion PNPs could provide a promising platform for the molecular diagnosis and targeting treatment of aortic valve disease. Targeting combination Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China

Collagen analysis of the ascending aortic dilatation associated with bicuspid aortic valve disease compared with tricuspid aortic valve

2016 ◽  
Vol 122 (5) ◽  
pp. 289-294 ◽  
Author(s):  
Alexander Navarrete Santos ◽  
Junfeng Yan ◽  
Peter Lochmann ◽  
Heike Pfeil ◽  
Michael Petersen ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
Aortic Dilatation ◽  
Tricuspid Aortic Valve ◽  
Collagen Analysis

scholarly journals Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

2017 ◽  
Vol 114 (7) ◽  
pp. 1631-1636 ◽  
Author(s):  
Qingchun Zeng ◽  
Rui Song ◽  
David A. Fullerton ◽  
Lihua Ao ◽  
Yufeng Zhai ◽  
...  
Keyword(s):  
Aortic Valve ◽  
High Fat Diet ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
High Fat ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Valve Lesions ◽  
Osteogenic Factors

Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease.

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.

scholarly journals Hemodynamic Profiles Before and After Surgery in Bicuspid Aortic Valve Disease—A Systematic Review of the Literature

2021 ◽  
Vol 8 ◽  
Author(s):  
Daniel G. W. Cave ◽  
Hannah Panayiotou ◽  
Malenka M. Bissell
Keyword(s):  
Systematic Review ◽  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Valve Disease ◽  
Flow Patterns ◽  
Valve Disease ◽  
Aortic Dilatation ◽  
4D Flow Mri ◽  
4D Flow ◽  
Flow Mri

Bicuspid aortic valve (BAV) disease presents a unique management challenge both pre- and post-operatively. 4D flow MRI offers multiple tools for the assessment of the thoracic aorta in aortic valve disease. In particular, its assessment of flow patterns and wall shear stress have led to new understandings around the mechanisms of aneurysm development in BAV disease. Novel parameters have now been developed that have the potential to predict pathological aortic dilatation and may help to risk stratify BAV patients in future. This systematic review analyses the current 4D flow MRI literature after aortic valve and/or ascending aortic replacement in bicuspid aortic valve disease. 4D flow MRI has also identified distinct challenges posed by this cohort at the time of valve replacement compared to standard management of tri-leaflet disorders, and may help tailor the type and timing of replacement. Eccentric pathological flow patterns seen after bioprosthetic valve implantation, but not with mechanical prostheses, might be an important future consideration in intervention planning. 4D flow MRI also has promising potential in supporting the development of artificial valve prostheses and aortic conduits with more physiological flow patterns.

Abstract 2069: Aortic Valve Replacement In Patients With Bicuspid Aortic Valve Disease Is Not Followed By Progressive Aortic Dilatation: A 15-year Study

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Ayyaz Ali ◽  
Amit Patel ◽  
Darren Freed ◽  
Yasir Abu-Omar ◽  
Ahmad Y Sheikh ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
Aortic Diameter ◽  
Implantation Technique ◽  
Aortic Dilatation ◽  
Aortic Pathology ◽  
Ascending Aortic Diameter

Objectives A bicuspid aortic valve may be associated with an aortopathy, this may lead to progressive aortic dilatation over time. It is uncertain whether the ascending aorta should be replaced prophylactically during AVR in these patients. We analyzed change in ascending aortic diameter following AVR, to determine whether a clinically important aortic pathology exists in patients with bicuspid aortic valve disease. Methods Demographic, operative and clinical data were obtained retrospectively through casenote review. AVR was performed using a homograft or porcine stentless valve using the subcoronary implantation technique. Patients were grouped according to whether their native aortic valve was identified as tricuspid (TC) or bicuspid (BC) at operation. Serial transthoracic echocardiograms were analyzed to measure pre-operative and post-operative ascending aortic diameter. Results 217 patients underwent AVR between 1 st January 1991 and 1 st January 2001. Ninety patients had a bicuspid aortic valve, in the remaining 127 the valve was tricuspid. The bicuspid group was younger ( BC 62yr +/− 15, TC 71yr +/− 12 yrs; p < 0.001). Follow-up echocardiography was performed 6.0 +/− 4.3 years post-operatively. Pre-operative ascending aortic diameter was similar (BC 3.2 +/− 0.5, TC 3.2 +/− 0.5 cm; p = 0.56) There was no difference in the increase in ascending aortic diameter over follow-up (BC 0.1 +/− 0.5, TC 0.0 +/− 0.5 cm; p = 0.34) Conclusion The clinical importance of “bicuspid aortopathy” in an older age group appears to be minimal. Additional aortic procedures designed to protect against progressive aortic aneurysmal disease in this setting are not justified.

Abstract 6147: A Tissue Stem Cell Niche Regulates Bicuspid Aortic Valve Disease

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Nalini M Rajamannan
Keyword(s):  
Stem Cell ◽  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Cross Talk ◽  
Aortic Valve Disease ◽  
Stem Cell Niche ◽  
Ex Vivo ◽  
Valve Disease ◽  
Aortic Valves ◽  
Cell Niche

Bicuspid aortic valve disease is the most common congenital cardiac malformation and indication for surgery for aortic valve patients. The age of onset for the development of stenosis is earlier in bicuspid aortic valves than tricuspid aortic valves. Understanding the cellular mechanisms of this valve lesion, will help to develop novel approaches towards slowing disease progression. This study hypothesizes that bicuspid aortic valve disease develops secondary to a tissue stem cell niche to activate a cross-talk mechanism which induces Notch1 cleavage and Lrp5 mediated bone formation specific to the bicuspid aortic valve. Human ex vivo bicuspid valves versus control aortic valves were tested for Notch1 expression by RTPCR, Western Blot and Immunohistochemistry. eNOS null bicuspid mice: control (n=20), cholesterol (n=20), cholesterol + Atorvastatin (n=20), were tested for the development of aortic stenosis by Visual Sonics Echo, Immunohistochemistry for Notch1, Wnt, Lrp5, Osteocalcin, PCNA and RTPCR for Notch1, Lrp5, Cbfa1, Osteocalcin. In vitro studies were performed to characterize Wnt secretion from aortic valve endothelial cells and gene expression for Notch1, Lp5 and osteocalcin from the valve myofibroblast cells. This study characterizes the secretion of Wnt3a (>300-fold, p<0.01) from aortic valve endothelium in the presence of abnormal nitric oxide regulation and lipids as measured by eNOS enzymatic activity and tissue nitrite levels. Osteoblastogenesis in the adjacent myofibroblast cell is activated via Notch1 cleavage(p<0.001) and upregulation of the Wnt3a/Lrp5 receptor. Human ex vivo valves express Notch1 cleavage as compared to normal valves from heart transplant(p<0.01). Cholesterol treated eNOS mice develop severe stenosis with cleavage of Notch1, increase in Lrp5, Wnt3a, cyclin, Cbfa1, and Osteopontin,(3-fold increase(p<0.01) which was not present in the controls and normalized in the statin treated valves. Targeting the Notch1/Wnt3a/Lrp5 pathway in bicuspid valvular calcification presents a novel approach towards treating this disease. The importance of this cross talk mechanism is demonstrated in three models of aortic valve disease and will have important clinical implications. This research has received full or partial funding support from the American Heart Association, AHA National Center.

scholarly journals Early Aberrant Angiogenesis Due to Elastic Fiber Fragmentation in Aortic Valve Disease

2021 ◽  
Vol 8 (7) ◽  
pp. 75
Author(s):  
Robert B. Hinton ◽  
Amy L. Juraszek ◽  
Amy M. Opoka ◽  
Benjamin J. Landis ◽  
J. Michael Smith ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Marfan Syndrome ◽  
Early Onset ◽  
Aortic Valve Disease ◽  
Late Onset ◽  
Elastic Fiber ◽  
Valve Disease ◽  
Aortic Valves ◽  
Valve Tissue ◽  
Fiber Fragmentation

Elastic fiber fragmentation (EFF) is a hallmark of aortic valve disease (AVD), and neovascularization has been identified as a late finding related to inflammation. We sought to characterize the relationship between early EFF and aberrant angiogenesis. To examine disease progression, regional anatomy and pathology of aortic valve tissue were assessed using histochemistry, immunohistochemistry, and electron microscopy from early-onset (<40 yo) and late-onset (≥40 yo) non-syndromic AVD specimens. To assess the effects of EFF on early AVD processes, valve tissue from Williams and Marfan syndrome patients was also analyzed. Bicuspid aortic valve was more common in early-onset AVD, and cardiovascular comorbidities were more common in late-onset AVD. Early-onset AVD specimens demonstrated angiogenesis without inflammation or atherosclerosis. A distinct pattern of elastic fiber components surrounded early-onset AVD neovessels, including increased emilin-1 and decreased fibulin-5. Different types of EFF were present in Williams syndrome (WS) and Marfan syndrome (MFS) aortic valves; WS but not MFS aortic valves demonstrated angiogenesis. Aberrant angiogenesis occurs in early-onset AVD in the absence of inflammation, implicating EFF. Elucidation of underlying mechanisms may inform the development of new pharmacologic treatments.

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.

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