scholarly journals Prognostic factors for progression of early- and late-stage calcific aortic valve disease in Japanese: The Japanese Aortic Stenosis Study (JASS) Retrospective Analysis

2010 ◽  
Vol 33 (3) ◽  
pp. 269-274 ◽  
Author(s):  
Kazuhiro Yamamoto ◽  
Hideya Yamamoto ◽  
Kiyoshi Yoshida ◽  
Akira Kisanuki ◽  
Yutaka Hirano ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Aortic Valve ◽  
Aortic Stenosis ◽  
Retrospective Analysis ◽  
Late Stage ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
Calcific Aortic Valve Disease

scholarly journals Metabolomics in Severe Aortic Stenosis Reveals Intermediates of Nitric Oxide Synthesis as Most Distinctive Markers

2021 ◽  
Vol 22 (7) ◽  
pp. 3569
Author(s):  
Beau Olivier van van Driel ◽  
Maike Schuldt ◽  
Sila Algül ◽  
Evgeni Levin ◽  
Ahmet Güclü ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Surgery ◽  
Aortic Valve ◽  
Aortic Stenosis ◽  
Western Blot ◽  
Aortic Valve Disease ◽  
Metabolic Profile ◽  
Valve Disease ◽  
Healthy Controls ◽  
Calcific Aortic Valve Disease

Background: Calcific aortic valve disease (CAVD) is a rapidly growing global health problem with an estimated 12.6 million cases globally in 2017 and a 112% increase of deaths since 1990 due to aging and population growth. CAVD may develop into aortic stenosis (AS) by progressive narrowing of the aortic valve. AS is underdiagnosed, and if treatment by aortic valve replacement (AVR) is delayed, this leads to poor recovery of cardiac function, absence of symptomatic improvement and marked increase of mortality. Considering the current limitations to define the stage of AS-induced cardiac remodeling, there is need for a novel method to aid in the diagnosis of AS and timing of intervention, which may be found in metabolomics profiling of patients. Methods: Serum samples of nine healthy controls and 10 AS patients before and after AVR were analyzed by untargeted mass spectrometry. Multivariate modeling was performed to determine a metabolic profile of 30 serum metabolites which distinguishes AS patients from controls. Human cardiac microvascular endothelial cells (CMECs) were incubated with serum of the AS patients and then stained for ICAM-1 with Western Blot to analyze the effect of AS patient serum on endothelial cell activation. Results: The top 30 metabolic profile strongly distinguishes AS patients from healthy controls and includes 17 metabolites related to nitric oxide metabolism and 12 metabolites related to inflammation, in line with the known pathomechanism for calcific aortic valve disease. Nine metabolites correlate strongly with left ventricular mass, of which three show reversal back to control values after AVR. Western blot analysis of CMECs incubated with AS patient sera shows a significant reduction (14%) in ICAM-1 in AS samples taken after AVR compared to AS patient sera before AVR. Conclusion: Our study defined a top 30 metabolic profile with biological and clinical relevance, which may be used as blood biomarker to identify AS patients in need of cardiac surgery. Future studies are warranted in patients with mild-to-moderate AS to determine if these metabolites reflect disease severity and can be used to identify AS patients in need of cardiac surgery.

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.

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.

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.

Late-stage Calcific Aortic Valve Disease Within an Aortic Valve-on-a-chip Model

2021 ◽  
Vol 5 (sup1) ◽  
pp. 69-70
Author(s):  
Melissa Mendoza ◽  
Mei-Hsiu Chen ◽  
Bruce Murray ◽  
Peter Huang ◽  
Gretchen Mahler
Keyword(s):  
Aortic Valve ◽  
Late Stage ◽  
Aortic Valve Disease ◽  
Valve Disease ◽  
Calcific Aortic Valve Disease

scholarly journals Evogliptin Suppresses Calcific Aortic Valve Disease by Attenuating Inflammation, Fibrosis, and Calcification

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 57
Author(s):  
Bongkun Choi ◽  
Eun-Young Kim ◽  
Ji-Eun Kim ◽  
Soyoon Oh ◽  
Si-On Park ◽  
...  
Keyword(s):  
Animal Models ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Rabbit Model ◽  
Cytokine Expression ◽  
Rate Of Change ◽  
Valve Disease ◽  
High Cholesterol Diet ◽  
Calcific Aortic Valve Disease ◽  
Valvular Calcification

Calcific aortic valve disease (CAVD) accompanies inflammatory cell infiltration, fibrosis, and ultimately calcification of the valve leaflets. We previously demonstrated that dipeptidyl peptidase-4 (DPP-4) is responsible for the progression of aortic valvular calcification in CAVD animal models. As evogliptin, one of the DPP-4 inhibitors displays high specific accumulation in cardiac tissue, we here evaluated its therapeutic potency for attenuating valvular calcification in CAVD animal models. Evogliptin administration markedly reduced calcific deposition accompanied by a reduction in proinflammatory cytokine expression in endothelial nitric oxide synthase-deficient mice in vivo, and significantly ameliorated the mineralization of the primary human valvular interstitial cells (VICs), with a reduction in the mRNA expression of bone-associated and fibrosis-related genes in vitro. In addition, evogliptin ameliorated the rate of change in the transaortic peak velocity and mean pressure gradients in our rabbit model as assessed by echocardiography. Importantly, evogliptin administration in a rabbit model was found to suppress the effects of a high-cholesterol diet and of vitamin D2-driven fibrosis in association with a reduction in macrophage infiltration and calcific deposition in aortic valves. These results have indicated that evogliptin prohibits inflammatory cytokine expression, fibrosis, and calcification in a CAVD animal model, suggesting its potential as a selective therapeutic agent for the inhibition of valvular calcification during CAVD progression.

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.

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