Abstract 288: Mice With Disruptive Egfr Signaling In The Aortic Valves Develop Calcific Aortic Valve Stenosis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Bin Zhou ◽  
Bingruo Wu
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Stenosis ◽  
Clinical Importance ◽  
Interstitial Cells ◽  
Left Ventricular ◽  
Specific Gene ◽  
Egfr Signaling ◽  
Aortic Valves ◽  
Major Health Problem ◽  
Mesenchymal Transition

Calcific aortic valve stenosis is a major health problem. Despite its clinical importance, the pathogenesis of this condition remains illusive. Aortic valves are made of endothelial cells and interstitial cells, both are derived from the endocardial cells of the heart during development. We have developed a new mouse model, Nfatc1-Cre, to specifically study the biology of the valve cells during valve development. In this study, we deleted epidermal growth factor receptor (Egfr) in the aortic valves using the Nfatc1-Cre and showed by histological and biochemical analyses that this deletion caused a spectrum of pathological characteristics of human calcific aortic valve stenosis. They include increased proliferation and dedifferentiation of the valve interstitial cells, abnormal deposition of extracellular matrix, bone-like formation and calcification. The null mice eventually developed the left ventricular dysfunction, presumably secondary to the stenotic aortic valves. We also revealed by immunohistochemistry and quantitative RT-PCR the changes in gene expression involved in the epithelial-to-mesenchymal transition or osteogenic activities. Altogether, these results demonstrate that Egfr signaling in the valve endothelial and interstitial cells regulates the homeostasis of the aortic valves and suggest that patients with mutations or medications affecting the Egfr signaling may be at the risk to develop calcific aortic valve stenosis. Our study also provides the proof-of-principle data showing that the Nfatc1-Cre is a useful genetic tool to elucidate the valve-specific gene function involved in the valve homeostasis and disease.

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.

scholarly journals Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice

2009 ◽  
Vol 297 (1) ◽  
pp. H65-H75 ◽  
Author(s):  
Cordelia J. Barrick ◽  
Reade B. Roberts ◽  
Mauricio Rojas ◽  
Nalini M. Rajamannan ◽  
Carolyn B. Suitt ◽  
...  
Keyword(s):  
Heart Failure ◽  
Aortic Valve ◽  
Left Ventricular Hypertrophy ◽  
Aortic Stenosis ◽  
Ventricular Hypertrophy ◽  
Left Ventricular ◽  
Egfr Signaling ◽  
Aortic Valves ◽  
Calcific Aortic Stenosis ◽  
Cardiac Phenotype

Epidermal growth factor receptor (EGFR) signaling contributes to aortic valve development in mice. Because developmental phenotypes in Egfr-null mice are dependent on genetic background, the hypomorphic Egfr wa2 allele was made congenic on C57BL/6J (B6) and 129S1/SvImJ (129) backgrounds and used to identify the underlying cellular cause of EGFR-related aortic valve abnormalities. Egfr wa2/wa2 mice on both genetic backgrounds develop aortic valve hyperplasia. Many B6- Egfr wa2/wa2 mice die before weaning, and those surviving to 3 mo of age or older develop severe left ventricular hypertrophy and heart failure. The cardiac phenotype was accompanied by significantly thicker aortic cusps and larger transvalvular gradients in B6- Egfr wa2/wa2 mice compared with heterozygous controls and age-matched Egfr wa2 homozygous mice on either 129 or B6129F1 backgrounds. Histological analysis revealed cellular changes in B6- Egfr wa2/wa2 aortic valves underlying elevated pressure gradients and progression to heart failure, including increased cellular proliferation, ectopic cartilage formation, extensive calcification, and inflammatory infiltrate, mimicking changes seen in human calcific aortic stenosis. Despite having congenitally enlarged valves, 129 and B6129F1- Egfr wa2/wa2 mice have normal lifespans, absence of left ventricular hypertrophy, and normal systolic function. These results show the requirement of EGFR activity for normal valvulogenesis and demonstrate that dominantly acting genetic modifiers curtail pathological changes in congenitally deformed valves. These studies provide a novel model of aortic sclerosis and stenosis and suggest that long-term inhibition of EGFR signaling for cancer therapy may have unexpected consequences on aortic valves in susceptible individuals.

Dissolving cholesterol crystals reduces aortic valve stenosis development in mice

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S.T Niepmann ◽  
M Lenart ◽  
N Willemsen ◽  
P Duewell ◽  
D Luetjohann ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Stenosis ◽  
Serum Cholesterol ◽  
Cholesterol Metabolism ◽  
Therapeutic Option ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Funding Source ◽  
Aortic Valves ◽  
Cholesterol Crystals

Abstract Background Aortic valve stenosis (AS) is the most common valve disease worldwide and is associated with a very high morbidity and mortality. Until today, aortic valve replacement is the only therapeutic option available. Analysis of explanted human aortic valves has shown that atherosclerosis-like lesions, that contain cholesterol crystals (CC), are present in stenotic aortic valve cusps. It has been demonstrated that CCs can activate the NLRP3 inflammasome and hereby trigger a complex, IL-1b driven, inflammatory response. 2-hydroxypropyl-β-cyclodextrin (CD) is a cyclic oligosaccharide that can increase the solubility of CCs, which results in a reduction of CC-load and therefore could inhibit the pro-inflammatory immune response. Methods Severe AS was induced in 10 weeks old C57BL/6-J (WT) and Apolipoprotein-E-deficient (ApoE) mice. Acoronary springwire was used to induce an endothelial injury under echocardiographic guidance. AS development was confirmed via ultrasound examinations. ApoE mice were fed a cholesterol-rich western diet and concomitantly received daily injections of 2g/kg/d CD via subcutaneous injection. CCs were visualized with laser reflection confocal microscopy. Serum cholesterol analysis were performed via mass GC-MS-SIM. Results In order to evaluate whether hyperlipidemia aggravates AS development, WT and ApoE mice were fed a cholesterol-rich diet and subjected to our model of wire-induced AS. Trans-aortic valve peak velocity levels of ApoE mice were significantly increased six weeks after injury compared to WT mice. Histological analysis of these mice showed large CC-deposits in the aortic valves of ApoE mice. Next, CC solubility was increased in a group of ApoE mice, control mice only received PBS injections. Interestingly, mice treated with CD displayed a significantly reduced peak blood velocity over the aortic valve compared to PBS mice. Left ventricular ejection fraction remained unchanged. Serum cholesterol analysis was performed to analyze the effect of CD on cholesterol metabolism. 27-hydroxycholesterol, an endogenous oxysterol of cholesterol metabolism, which reduces the potential for the conversion of free cholesterol into crystals was significantly increased in CD treated mice. The levels of cholesterol precursors were unchanged, indicating that CD doesn't influence de-novo synthesis of cholesterol. Intestinal absorption of cholesterol was also not affected by CD, as assessed by quantification of phytosterols in the serum of CD and PBS treated mice. Conclusion These results underline the importance of hyperlipidemia in the pathogenesis of AS. Particularly CCs seem to act as an important inflammatory trigger in the development of AS. Increasing the solubility of cholesterol through CD reduces AS development in mice and could, as it is already considered safe in human, act as a possible therapeutic option. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): DFG, German Research Foundation

Left Ventricular Remodeling in Degenerative Aortic Valve Stenosis

2021 ◽  
Vol 46 (5) ◽  
pp. 100801
Author(s):  
João Abecasis ◽  
Daniel Gomes Pinto ◽  
Sância Ramos ◽  
Pier Giorgio Masci ◽  
Nuno Cardim ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Stenosis ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular

Presence of adipose tissue in aortic valves from aortic regurgitation patients: pathophysiological role and clinical implications

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Sadaba Cipriain ◽  
A.M Navarro Echeverria ◽  
C.R Tiraplegui Garjon ◽  
A Garcia De La Pena Urtasun ◽  
V Arrieta Paniagua ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Aortic Valve ◽  
Aortic Regurgitation ◽  
Systolic Function ◽  
Statistical Significance ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Funding Source ◽  
Matrix Remodeling ◽  
Aortic Valves

Abstract Introduction Adipose tissue is a common constituent of the heart and it is located, without great clinical relevance, frequently in the pericardium. The presence of adipose tissue in the aortic valve is rare, with unknown significance on valve structural properties and function. Aortic regurgitation (AR) is the third most prevalent valve disease, although it is uncommon to find it in isolation. Myxoid degeneration may be the cause or result of AR, although the pathophysiology remains poorly understood. Purpose To describe and characterize the presence of adipose tissue in the aortic valves from a cohort of AR patients. Methods 116 patients undergoing aortic valve replacement due to severe AR were enrolled. We classified them in two groups according to the histological results showing presence or absence of adipose tissue in the aortic valves. In the valve tissue molecular analysis were performed by RT-PCR, Western Blot and ELISA to analyze markers of adipocytes (leptin, adiponectin, resistin), inflammation (Rantes, interleukin-6, interleukin-1β), extracellular matrix remodeling (metalloproteinases-1, -2 and -9), proteoglycans (aggrecan, hyaluronan, lumican, syndecan-1, decorin) and fibrosis (collagens, fibronectin). Results Adipose tissue was found in 63% of the aortic valves analyzed. Baseline characteristics (age, hypertension, dyslipidemia, diabetes, smoking, left ventricular telediastolic diameter, left ventricular systolic function, ascending aorta) were similar in patients presenting valve adipose tissue as compared with patients without valve adipose tissue. Valves containing adipocytes exhibited a higher leptin content (p<0.001), fibronectin (p<0.01), decorin (p<0,0001), hyaluronan (p=0.03), aggrecan (p=0.04) and metalloproteinase 1 (p=0.03). Interestingly, the presence of adipocytes in the valve was positively correlated with valve thickness measured by echocardiogram (Pearson chi2 statistical significance = 26.3345 p<0.001). Conclusion To our knowledge, this is the first study that describes the presence of adipose cells in aortic valves from a cohort of AR patients. Aortic valves containing adipocytes were thicker and exhibited significant higher levels of proteoglycans, suggesting that adipocytes could contribute to the myxomatous degeneration process. Our results propose that the valve adipose tissue could play a role in the pathophysiology of AR. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Gobierno de Navarra

Unicommissural aortic valve in neonates and its association with other congenital heart disease

1995 ◽  
Vol 5 (2) ◽  
pp. 132-139 ◽  
Author(s):  
Ana C. Durán ◽  
Luciano Daliento ◽  
Carla Frescura ◽  
Giovanni Stellin ◽  
Valentín Sans-Coma ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Coarctation Of The Aorta ◽  
Left Ventricular ◽  
Etiologic Factor ◽  
Fetal Life ◽  
Aortic Valves ◽  
Flow Through ◽  
And Gender ◽  
University Of Padua ◽  
Congenital Aortic Valvar Stenosis

AbstractThe morphology of the aortic valve was studied in 1,022 heart specimens belonging to the collection of the Institute of Pathological Anatomy, University of Padua. Twenty specimens were found to have a unicommissural aortic valve, characterized by the presence of a single leaflet with only one functional commissure; however, the presence of two raphes enabled the recognition of a basically three-sinus arrangement. Age and gender were known in 19 cases: 14 male and five female, mean age nine days. In 19 cases, the unicommissural valve was dysplastic and resulted in a severe congenital aortic valvar stenosis. Only in two hearts was the unicommissural nature of the aortic valve an isolated finding; among the remaining 18, left ventricular fibroelastosis in 11, malformation of the mitral valve in 11, hypoplasia of the left ventricle in eight, ventricular septal defect in four, mitral atresia in three, and subaortic fibrous diaphragm in one. Furthermore, seven (35%) of these 20 unicommissural aortic valves were associated with coarctation of the aorta. Statistical analysis shows that this association is not a random event. Our findings support the hypothesis that the unicommissural aortic valve originates from the early fusion of the three mesenchymal valvar cushions or leaflet primordia. Although the present data do not exclude the possibility that reduction of the blood flow through the aorta during fetal life may play a role in the formation of the unicommissural aortic valve, they rather point in the direction that another etiologic factor, such as an anomalous migration of neural crest cells, may be responsible for the fusion of the valvar cushions.

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