scholarly journals Dissecting Calcific Aortic Valve Disease—The Role, Etiology, and Drivers of Valvular Fibrosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Petra Büttner ◽  
Lukas Feistner ◽  
Philipp Lurz ◽  
Holger Thiele ◽  
Joshua D. Hutcheson ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Molecular Mechanisms ◽  
Left Ventricular ◽  
Valve Disease ◽  
Reverse Remodeling ◽  
Calcific Aortic Valve Disease ◽  
Ecm Remodeling ◽  
The Individual

Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorder that ultimately causes gradual narrowing of the left ventricular outflow orifice with ensuing devastating hemodynamic effects on the heart. Calcific mineral accumulation is the hallmark pathology defining this process; however, fibrotic extracellular matrix (ECM) remodeling that leads to extensive deposition of fibrous connective tissue and distortion of the valvular microarchitecture similarly has major biomechanical and functional consequences for heart valve function. Significant advances have been made to unravel the complex mechanisms that govern these active, cell-mediated processes, yet the interplay between fibrosis and calcification and the individual contribution to progressive extracellular matrix stiffening require further clarification. Specifically, we discuss (1) the valvular biomechanics and layered ECM composition, (2) patterns in the cellular contribution, temporal onset, and risk factors for valvular fibrosis, (3) imaging valvular fibrosis, (4) biomechanical implications of valvular fibrosis, and (5) molecular mechanisms promoting fibrotic tissue remodeling and the possibility of reverse remodeling. This review explores our current understanding of the cellular and molecular drivers of fibrogenesis and the pathophysiological role of fibrosis in CAVD.

scholarly journals Identification of key genes in calcific aortic valve disease via weighted gene co-expression network analysis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jin-Yu Sun ◽  
Yang Hua ◽  
Hui Shen ◽  
Qiang Qu ◽  
Jun-Yan Kan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Network Analysis ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Expression Profiles ◽  
Enrichment Analysis ◽  
Valve Disease ◽  
Hub Genes ◽  
Calcific Aortic Valve Disease ◽  
Underlying Mechanisms

Abstract Background Calcific aortic valve disease (CAVD) is the most common subclass of valve heart disease in the elderly population and a primary cause of aortic valve stenosis. However, the underlying mechanisms remain unclear. Methods The gene expression profiles of GSE83453, GSE51472, and GSE12644 were analyzed by ‘limma’ and ‘weighted gene co-expression network analysis (WGCNA)’ package in R to identify differentially expressed genes (DEGs) and key modules associated with CAVD, respectively. Then, enrichment analysis was performed based on Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, DisGeNET, and TRRUST database. Protein–protein interaction network was constructed using the overlapped genes of DEGs and key modules, and we identified the top 5 hub genes by mixed character calculation. Results We identified the blue and yellow modules as the key modules. Enrichment analysis showed that leukocyte migration, extracellular matrix, and extracellular matrix structural constituent were significantly enriched. SPP1, TNC, SCG2, FAM20A, and CD52 were identified as hub genes, and their expression levels in calcified or normal aortic valve samples were illustrated, respectively. Conclusions This study suggested that SPP1, TNC, SCG2, FAM20A, and CD52 might be hub genes associated with CAVD. Further studies are required to elucidate the underlying mechanisms and provide potential therapeutic targets.

scholarly journals Extracellular Matrix in Calcific Aortic Valve Disease: Architecture, Dynamic and Perspectives

2021 ◽  
Vol 22 (2) ◽  
pp. 913
Author(s):  
Anna Di Vito ◽  
Annalidia Donato ◽  
Ivan Presta ◽  
Teresa Mancuso ◽  
Francesco Saverio Brunetti ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Matrix Vesicles ◽  
Developed Countries ◽  
Valve Disease ◽  
Ageing Population ◽  
Calcific Aortic Valve Disease ◽  
Molecular Alterations ◽  
Active Processes

Calcific Aortic Valve Disease (CAVD) is the most common valvular heart disease in developed countries and in the ageing population. It is strongly correlated to median age, affecting up to 13% of the population over the age of 65. Pathophysiological analysis indicates CAVD as a result of an active and degenerative disease, starting with sclerosis and chronic inflammation and then leaflet calcification, which ultimately can account for aortic stenosis. Although CAVD has been firstly recognized as a passive event mostly resulting from a degenerative aging process, much evidences suggests that calcification arises from different active processes, involving both aortic valve-resident cells (valve endothelial cells, valve interstitial cells, mesenchymal stem cells, innate immunity cells) and circulating cells (circulating mesenchymal cells, immunity cells). Moreover, a role for the cell-derived “matrix vesicles” and extracellular matrix (ECM) components has also been recognized. The aim of this work is to review the cellular and molecular alterations occurring in aortic valve during CAVD pathogenesis, focusing on the role of ECM in the natural course of the disease.

scholarly journals Cellular and molecular mechanisms of calcific aortic valve disease

2019 ◽  
pp. 86-91
Author(s):  
E. V. Shcheglova ◽  
M. Kh. Baykulova ◽  
O. I. Boeva
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Molecular Mechanisms ◽  
Current Data ◽  
Valve Disease ◽  
Ectopic Calcification ◽  
Calcific Aortic Valve Disease ◽  
Initiation Phase ◽  
Replacement Surgery ◽  
Leading Role

The review provides current data on the pathogenesis of calcific aortic valve disease (CAVD) — a widespread disease with unfavorable prognosis. Currently, there are no effective therapeutic methods for the prevention and treatment of this pathology with the exception of valve replacement surgery. The role of genetic and hereditary factors in the occurrence of CAVD is considered, the leading pathogenetic mechanisms are described taking into account the stage of the disease. In particular, in the initiation phase of calcification, deposition of oxidized lipoproteins in the cusps and local inflammation plays the leading role. In the progression phase, active ectopic calcification dominates, similar to the process of bone formation. The study of the pathogenesis of CAVD seems appropriate taking into account the prospect of developing new effective therapeutic and prophylactic approaches.

scholarly journals Calcific Aortic Valve Disease: Molecular Mechanisms And Therapeutic Approaches

2015 ◽  
Vol 10 (2) ◽  
pp. 108 ◽  
Author(s):  
Daniel Alejandro Lerman ◽  
Sai Prasad ◽  
Nasri Alotti ◽  
◽  
◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Molecular Mechanisms ◽  
Cell Model ◽  
Human Monoclonal Antibody ◽  
Valve Disease ◽  
Vascular Lesions ◽  
Calcium Deposition ◽  
Calcific Aortic Valve Disease

Calcification occurs in atherosclerotic vascular lesions and in the aortic valve. Calcific aortic valve disease (CAVD) is a slow, progressive disorder that ranges from mild valve thickening without obstruction of blood flow, termed aortic sclerosis, to severe calcification with impaired leaflet motion, termed aortic stenosis. In the past, this process was thought to be ‘degenerative’ because of time-dependent wear and tear of the leaflets, with passive calcium deposition. The presence of osteoblasts in atherosclerotic vascular lesions and in CAVD implies that calcification is an active, regulated process akin to atherosclerosis, with lipoprotein deposition and chronic inflammation. If calcification is active, via pro-osteogenic pathways, one might expect that development and progression of calcification could be inhibited. The overlap in the clinical factors associated with calcific valve disease and atherosclerosis provides further support for a shared disease mechanism. In our recent research we used an in vitro porcine valve interstitial cell model to study spontaneous calcification and potential promoters and inhibitors. Using this model, we found that denosumab, a human monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand may, at a working concentration of 50 μg/mL, inhibit induced calcium deposition to basal levels.

scholarly journals Circulating and tissue matricellular RNA and protein expression in calcific aortic valve disease

2020 ◽  
Vol 52 (4) ◽  
pp. 191-199 ◽  
Author(s):  
Alexander P. Kossar ◽  
Wanda Anselmo ◽  
Juan B. Grau ◽  
Yichuan Liu ◽  
Aeron Small ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Aortic Valve ◽  
Aortic Stenosis ◽  
Protein Expression ◽  
Aortic Valve Disease ◽  
Severe Aortic Stenosis ◽  
Valve Disease ◽  
Circulating Biomarkers ◽  
Calcific Aortic Valve Disease ◽  
Aortic Valve Sclerosis

Aortic valve sclerosis is a highly prevalent, poorly characterized asymptomatic manifestation of calcific aortic valve disease and may represent a therapeutic target for disease mitigation. Human aortic valve cusps and blood were obtained from 333 patients undergoing cardiac surgery ( n = 236 for severe aortic stenosis, n = 35 for asymptomatic aortic valve sclerosis, n = 62 for no valvular disease), and a multiplex assay was used to evaluate protein expression across the spectrum of calcific aortic valve disease. A subset of six valvular tissue samples ( n = 3 for asymptomatic aortic valve sclerosis, n = 3 for severe aortic stenosis) was used to create RNA sequencing profiles, which were subsequently organized into clinically relevant gene modules. RNA sequencing identified 182 protein-encoding, differentially expressed genes in aortic valve sclerosis vs. aortic stenosis; 85% and 89% of expressed genes overlapped in aortic stenosis and aortic valve sclerosis, respectively, which decreased to 55% and 84% when we targeted highly expressed genes. Bioinformatic analyses identified six differentially expressed genes encoding key extracellular matrix regulators: TBHS2, SPARC, COL1A2, COL1A1, SPP1, and CTGF. Differential expression of key circulating biomarkers of extracellular matrix reorganization was observed in control vs. aortic valve sclerosis (osteopontin), control vs. aortic stenosis (osteoprotegerin), and aortic valve sclerosis vs. aortic stenosis groups (MMP-2), which corresponded to valvular mRNA expression. We demonstrate distinct mRNA and protein expression underlying aortic valve sclerosis and aortic stenosis. We anticipate that extracellular matrix regulators can serve as circulating biomarkers of early calcific aortic valve disease and as novel targets for early disease mitigation, pending prospective clinical investigations.

scholarly journals Electrocardiographic Pattern of Left Ventricular Hypertrophy with Strain and Survival in Calcific Aortic Valve Disease

2018 ◽  
Vol 2 (3) ◽  
pp. 240-246
Author(s):  
Edgard A. Prihadi ◽  
Melissa Leung ◽  
E. Mara Vollema ◽  
Arnold C. T. Ng ◽  
Nina Ajmone Marsan ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Left Ventricular Hypertrophy ◽  
Aortic Valve Disease ◽  
Ventricular Hypertrophy ◽  
Left Ventricular ◽  
Valve Disease ◽  
Calcific Aortic Valve Disease

scholarly journals Heat shock protein 90 is downregulated in calcific aortic valve disease

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jonna Weisell ◽  
Pauli Ohukainen ◽  
Juha Näpänkangas ◽  
Steffen Ohlmeier ◽  
Ulrich Bergmann ◽  
...  
Keyword(s):  
Heat Shock ◽  
Aortic Valve ◽  
Heat Shock Protein ◽  
Western Blot ◽  
Aortic Valve Disease ◽  
Molecular Mechanisms ◽  
Valve Disease ◽  
Control Group ◽  
Calcific Aortic Valve Disease ◽  
Data Set

Abstract Background Calcific aortic valve disease (CAVD) is an atheroinflammatory process; finally it leads to progressive calcification of the valve. There is no effective pharmacological treatment for CAVD and many of the underlying molecular mechanisms remain unknown. We conducted a proteomic study to reveal novel factors associated with CAVD. Methods We compared aortic valves from patients undergoing valvular replacement surgery due to non-calcified aortic insufficiency (control group, n = 5) to a stenotic group (n = 7) using two-dimensional difference gel electrophoresis (2D-DIGE). Protein spots were identified with mass spectrometry. Western blot and immunohistochemistry were used to validate the results in a separate patient cohort and Ingenuity Pathway Analysis (IPA) was exploited to predict the regulatory network of CAVD. Results We detected an upregulation of complement 9 (C9), serum amyloid P-component (APCS) and transgelin as well as downregulation of heat shock protein (HSP90), protein disulfide isomerase A3 (PDIA3), annexin A2 (ANXA2) and galectin-1 in patients with aortic valve stenosis. The decreased protein expression of HSP90 was confirmed with Western blot. Conclusions We describe here a novel data set of proteomic changes associated with CAVD, including downregulation of the pro-inflammatory cytosolic protein, HSP90.

scholarly journals Sex-Specific Features of Calcific Aortic Valve Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5620 ◽  
Author(s):  
Volha I. Summerhill ◽  
Donato Moschetta ◽  
Alexander N. Orekhov ◽  
Paolo Poggio ◽  
Veronika A. Myasoedova
Keyword(s):  
Aortic Valve ◽  
Aortic Stenosis ◽  
Aortic Valve Disease ◽  
The Elderly ◽  
Developed Countries ◽  
Left Ventricular ◽  
Valve Disease ◽  
Calcific Aortic Valve Disease ◽  
Men And Women ◽  
Increased Risk

Calcific aortic valve disease (CAVD) is the most common valvular heart disease in developed countries predominantly affecting the elderly population therefore posing a large economic burden. It is a gradually progressive condition ranging from mild valve calcification and thickening, without the hemodynamic obstruction, to severe calcification impairing leaflet motion, known as aortic stenosis (AS). The progression of CAVD occurs over many years, and it is extremely variable among individuals. It is also associated with an increased risk of coronary events and mortality. The recent insights into the CAVD pathophysiology included an important role of sex. Accumulating evidence suggests that, in patients with CAVD, sex can determine important differences in the relationship between valvular calcification process, fibrosis, and aortic stenosis hemodynamic severity between men and women. Consequently, it has implications on the development of different valvular phenotypes, left ventricular hypertrophy, and cardiovascular outcomes in men and women. Along these lines, taking into account the sex-related differences in diagnosis, prognosis, and treatment outcomes is of profound importance. In this review, the sex-related differences in patients with CAVD, in terms of pathobiology, clinical phenotypes, and outcomes were discussed.

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